Foetal Exposure and Epidemiological Transition: Role of Anaemia in Early Life for Non-communicable Diseases Later
Condition: Anemia and Pregnancy; Metabolism and Foetal Growth; Epigenetics
MeSH terms: Anemia; Noncommunicable Diseases
Study type: Observational [Patient Registry]

Summary: 
      Study Hypotheses:

        1. Anaemia, which is frequent before conception as well as during early pregnancy, affects
           metabolism and foetal growth trajectories, influencing the risk of NCDs in the
           offspring.

        2. Anaemia from conception till end of 2nd trimester is most detrimental for foetal and
           newborns' health, compared to 3rd trimester anaemia.

        3. Anaemia from conception till end of 2nd trimester affects foetal and newborns health
           through poor placental development reflected in increased villous branching and changed
           umbilical and uterine blood flow.

        4. Anaemia in early pregnancy disrupts the vascular endothelial growth factor A
           (VEGF-A)/placental growth factor (PlGF) balance and the insulin-like growth factor (IGF)
           axis resulting in poor placental development, and poor health of newborns. This may be
           reflected in specific methylation patterns.

        5. Anaemia's impact on the risk for NCDs in the offspring may be mediated via epigenetic
           mechanisms, including changes in DNA methylation patterns.
    

Detailed description: 
      Specific objectives are:

        1. Characterize the health of women aged 18-40 years before conception and during
           pregnancy, focusing on prevalence of anaemia, infections, nutritional status, and
           Non-Communicable Diseases (NCDs).

        2. Describe how 1st and 2nd trimester anaemia compared to 3rd trimester anaemia alters
           foetal growth and newborns' body composition.

        3. Evaluate how 1st and 2nd trimester anaemia compared to 3rd trimester anaemia affects
           villous branching in the placenta, as well as uterine and umbilical artery blood flow.

        4. Characterize how 1st, 2nd and 3rd trimester anaemia differentially changes the vascular
           endothelial growth factor A (VEGF-A)/placental growth factor (PlGF) balance and the
           insulin-like growth factor axis.

        5. Determine which markers for foetal programming such as methylation of regulatory genes
           related to metabolism and haematopoiesis may be discovered early after exposure to
           anaemia in1st and 2nd trimester compared to 3rd trimester anaemia.

      Outcome parameter for the pre-pregnancy study (i.): 1) Prevalence and severity of anaemia
      among non-pregnant Tanzanian women at fertile age and their nutritional status. 2) Incidence
      of conception among such women.

      Outcome parameter for the pregnancy study (ii.): 1) Foetal growth rate in 2nd and 3rd
      trimester in offspring of anaemic mothers vs Foetal growth rate in non-anaemic mothers'
      offspring, 2) Comparison of anaemic mothers' vs non-anaemic mothers' newborn's body
      composition, placental villous branching, umbilical and uterine blood flow, VEGF-A/PlGF
      levels, and insulin-like growth factor axis.

      For all analyses main exposure variable will be anaemia (Hb<5mmol/L) in 1st, 2nd and/or3rd
      trimester of pregnancy. Confounding exposure variables will be chronic health conditions
      (e.g. HIV), all temporary conditions mentioned above (e.g. malaria) as well as socioeconomic
      status and paternal characteristics. Regression modelling using both multiple linear and
      logistic regressions as well as modelling for repeated measures will be used for statistical
      analyses. For genetic and epigenetic changes, findings in the subgroup of 180 other/newborns,
      remaining significant after correction for multiple comparisons, will be validated in the
      remaining cohort. This will enable us within one study to replicate initial findings in one
      representative and distinct subgroup in another larger comparable study group from an overall
      homogenous study. Indeed, findings surviving both corrections for multiple testing in the
      initial hypothesis generating array approaches, as well as being replicated in the remaining
      study group with single target validation techniques, are highly likely to be biological
      important. Possible findings from the candidate gene approach will be corrected for multiple
      testing and the significant results will be compared with previous findings of the same genes
      from studies in muscle and adipose tissue conducted by Diabetes and Metabolism, Copenhagen
      University Hospital.
    

Observational model: Other
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Amendment October 2014: replacement of two-phase case-control study by two sub-projects,
        running in parallel, and following two distinct groups of women, 1) a cohort of 1500
        non-pregnant women, disregarding Hb level, of whom 270 followed throughout pregnancy
        disregarding Hb level and gestational age at first contact, and 2) a case control study of
        480 pregnant women followed from 1st trimester with a 160:160:160 ratio of women with
        Hb≤8g/dL: 8.1-10.9g/dL: ≥11g/dL.

        The Danish Council for Strategic Research notified and accepted in November 2014.
      
Biospecimen description: 
      Periperal vein blood, umbilical cord blood, placentas
    
Keywords: Anaemia; Pregnancy; Foetal programming; Epigenetics; Non-communicable diseases; Tanzania