Abstract |
Introduction:
Most organs and structures of the developing fetus are formed in the first months after
conception. Therefore, early pregnancy is highly recognized as a time period with significant
susceptibility to an adverse intrauterine environment. Beyond nutrition and other
environmental risk factors, maternal pre-pregnancy obesity has been associated with
increased risk of offspring obesity, adverse lipid profile and impaired glucose tolerance as
well as neurodevelopmental disorders in childhood and adulthood. However, little is known
about the potential impact of other parameters of the metabolic syndrome in early pregnancy
on metabolic programming and neurodevelopment in the offspring. Additionally, maternal
vitamin D levels are considered an essential biological factor for intrauterine skeletal growth
and muscle development, but limited data exist so far on the potential impact of circulating
vitamin D on offspring adiposity and mental development.
We aimed to investigate in greater detail the effect of metabolic dysregulation and maternal
25(OH)D levels in early pregnancy with multiple offspring metabolic and neuropsychological
outcomes at 4 years of age, in a prospective pregnancy cohort in Crete, Greece.
Specific Objectives:
1) To investigate the impact of components of metabolic syndrome in early pregnancy
on offspring cardiometabolic traits at 4 years of age.
2) To evaluate the role of components of metabolic syndrome in early pregnancy in
psychomotor development, and behavioral difficulties at 4 years of age.
3) To investigate the association of 25(OH)D levels in early pregnancy on offspring
cardiometabolic traits at preschool age.
4) To examine the impact of 25(OH)D levels in early pregnancy on cognitive and
psychomotor development at preschool age.
Methods: Our study population was part of the “Rhea” study, a prospective pregnancy
cohort, at the prefecture of Heraklion, Crete, Greece. Pregnant women were recruited at the
time of the first ultrasound examination, during the twelve-month period from February 2007
until February 2008. Women were contacted again at various times during pregnancy, at birth, and for child’s follow-up at 9th, 18th months, and at 4 and 6 years of age. Face-to face
completed questionnaires together with self-administered questionnaires and medical records
were used to obtain information on dietary, environmental, and psychosocial exposures
during pregnancy and early childhood. Maternal pre-pregnancy BMI was calculated by
maternal height, measured at the first prenatal visit, and pre-pregnancy weight, as reported at
the first ultrasound visit. At the first prenatal visit trained examiners measured maternal blood
pressure levels, and collected maternal serum samples for maternal glucose, lipid and
25(OH)D measurements. At 4 years of age data on child anthropometry, blood pressure
measures, and serum samples for offspring lipid measurements were collected by specially
trained research assistants, according to standard operating procedures. Αdditionally, at 6
years follow up offspring body composition was estimated, by a bioelectric impedance
analysis (BIA). Moreover, children’s cognitive and motor function at 4 years of age was
evaluated by two trained psychologists through the McCarthy Scales of Children Abilities.
Behavioral difficulties were assessed by Strengths and Difficulties Questionnaire and
Attention Deficit Hyperactivity Disorder Test, completed by mothers. Adjusted associations
were obtained via multivariable linear and logistic regression analyses.
Results: 1) In the analysis of the relationship between components of metabolic syndrome in
early pregnancy and cardiometabolic traits at preschool age, we found that maternal
overweight/obesity pre-pregnancy was associated with increased risk of offspring
overweight/obesity, central adiposity, and greater fat mass at 4 years of age, predominantly in
girls. In addition, an increase of 40mg/dl in fasting serum cholesterol levels in early
pregnancy was also associated with increased risk of overweight/obesity and fat mass in
preschoolers. The associations remained the same after adjustment for several maternal and
child characteristics, including maternal BMI. Seemingly a significant positive association
was observed between higher levels of maternal diastolic blood pressure and adiposity
measures at 4 years of age. 2) Among maternal metabolic diseases examined, only maternal
overweight/obesity pre-pregnancy was associated with a significant score reduction in
perceptual performance, quantitative ability, general cognitive function, and executive
functions at 4years of age. In addition maternal overweight/obesity pre-pregnancy was
associated with significant increment in behavioral problems and ADHD-like symptoms at
preschool age. The observed associations remained significant after adjustment for several
confounders, including paternal BMI. 3) In our analysis for the impact of maternal 25(OH)D status on offspring health outcomes at preschool age, about two-thirds of participating women
suffered from vitamin D deficiency in the first half of pregnancy. Offspring of mothers with
25(OH)D levels in the lower tertile had significantly increased BMI SD score, central
adiposity and body fat percentage at 4 years of age, compared to offspring of mothers with
higher 25(OH)D levels. 4) In contrast increased maternal 25(OH)D levels in early pregnancy
seemed to protect from behavioral problems in early childhood, as offspring of women with
25(OH)D levels in the high tertile had significantly decreased hyperactivity/impulsivity and
total ADHD-like symptoms, as well as decreased total behavioral difficulties at 4 years of
age, compared to offspring of women with 25(OH)D levels in the low tertile. Τhe observed
associations remained the same after adjustment for several confounders and maternal BMI,
and were more pronounced in girls than in boys.
Conclusions: In summary, findings in the present thesis support the view that maternal
metabolic dysregulation and vitamin D status in early pregnancy may have an important
impact on offspring adiposity measures and neurodevelopmental outcomes in early
childhood, independently of sociodemographic and family parameters. Our results may have
important public health implications, as the examined exposures are modifiable risk factors
and may be prevented with appropriate awareness and guidance. Further follow-up of this
cohort will allow to determine whether our findings persist at later ages.
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