Cord Blood Lipid Levels Linked to Birth Weight, Doppler Velocimetry of Fetal Vessels in Fetal Growth Restriction Pregnancies

Background: role of lipid metabolism in placental, umbilical cord blood for fetal growth restriction pregnancies

A developing fetus relies on uteroplacental circulation to receive oxygen and nutrients for growth throughout the 40-week gestational period. Impairments to uteroplacental and umbilical blood flow, called uteroplacental insufficiency, is the leading cause of fetal growth restriction.

Fetal growth restriction is defined as fetus that does not reach its genetic growth potential and complications can significantly impact morbidity, including:

• Increased short-term health risks
• Prematurity
• Poor thermoregulation
• Feeding intolerance
• Organ dysfunction
• Sepsis
• Increased long-term health risks
• Metabolic
• Cardiovascular
• Neurodevelopment

Doppler velocimetry is used to monitor fetal circulation in high-risk pregnancies and abnormalities in fetal vessels are associated with fetal compromise in utero.

Impaired uteroplacental and umbilical blood flow in fetal growth restriction can affect the function of the placenta to transport amino acids, sodium/potassium, glucose and calcium from the mother to the fetus. It is not well understood how lipids –– vital for growth and development –– are metabolized in fetal growth restricted pregnancies.

Past research by study authors demonstrated:

• Upregulation of placental fatty acid transport proteins
• Increase in long-chain polyunsaturated fatty acids (LCPUFA) stored as triglycerides in human fetal growth restriction placentas

Fetal fat deposition increases exponentially across gestation during pregnancy, reaching the maximum accumulation at term.

• Fat stores serve as a significant source of essential lipids in early extrauterine life
• Fetal growth-restricted fetuses are at risk for very decreased subcutaneous fat depots
  • Often depends on the severity of growth restriction
  • Can negatively impact early postnatal life
• LCPUFA are vital for brain and retinal development
  • For normal brain development:
    • Must transfer across the placenta from maternal circulation, and
    • Adequately accumulate in fetal fat deposits

A multi-disciplinary team of researchers, including Stephanie Chassen, MD, Karin Zemski-Berry, PhD, John Hobbins, MD, and Theresa L. Powell, PhD, from Children’s Hospital Colorado and the University of Colorado School of Medicine, sought to determine:

• Concentrations of fatty acids, complex lipid molecules in placenta and umbilical cord blood from fetal growth restriction infants and small for gestational age controls
• Associations between levels, measures of fetal growth, wellbeing

They hypothesized:

• Triglyceride concentrations are increased in placentas
• Important complex lipids are reduced in cord plasma from pregnancies producing the smallest babies in correlation with ultrasound Dopplers

Methods: comparison of fetal growth-restricted infants with small for gestational age controls

Study criteria:

• Pregnant with singleton fetus <10th percentile fetal weight for gestational age
• 2nd or 3rd trimester
• >18 years old
• <20-week ultrasound with no fetal, chromosomal anomalies
• Delivered at University of Colorado Hospital
• Placentas and cord blood were collected

Dopplers longitudinally assessed pregnancies with estimated fetal weight < 10% at 29 weeks’ gestation by measuring:

• Umbilical artery (UA) pulsatility index (PI)
• Middle cerebral artery (MCA) pulsatility index (PI)
• Cerebroplacental ratio (CPR)-MCA PI divided by UA PI

Results: differences in fetal growth restricted and small for gestational age infants

When compared to small for gestational age controls, the analysis found fetal growth restricted infants at birth were:

• Delivered 1 week earlier
• 29% smaller in weight (average birth weight percentile of 2.88%)
• 133% higher UA PI
• 10% shorter in length
• Significantly increased head circumference to birth weight ratio

Fatty acid and lipid concentrations in umbilical veinplasma

• Few significant differences in phosphatidylcholine (PC) concentrations between groups
• Lysophosphatidylcholine (LPC) analysis found pattern of lower concentrations in fetal growth restriction group across measured lipid species
  • Significant differences in LPCs containing:
    • Palmitoleic acid
    • Docosapentaenoic acid
    • DHA – DHA-LPC 50% lower in fetal growth restricted umbilical vein
  • Non-esterified fatty acid concentrations in fetal growth restriction cord plasma
    • Increase in:
  • Palmitic
  • Alpha-linolenic
  • Oleic
  • Stearic
  • Arachidonic acids
    • No change in DHA
  • Arachidonic acid-derived eicosanoid molecule panel analysis found fetal growth restricted infants had significantly increased concentrations of
    • 5- and 12-hydroxyeicosatetraenoic acid
    • All three measured epoxyeicosatrienoic acid molecules

Correlations between plasma lipid concentrations and birth weight z-scores

• Inverse correlations:
  • Almost all measured triglyceride species most likely to contain LCPUFAs
  • 2 epoxyeicosatrienoic acid (EET) eicosanoids
• Direct correlations:
  • LPCs containing LCPUFA

Correlations between plasma lipid concentrations and Doppler indices

• UA PI
  • Inverse correlation with LPCs containing LCPUFAs
  • Direct correlations with:
    • Eicosanoid EET molecules
    • Non-esterified arachidonic acid and DHA
  • CPR
    • Direct correlation with LCPUFA-LPCs

Fatty acid and lipid concentrations in placenta homogenate

• Minimal significant differences of placental homogenate of lipid molecules between groups
• Significantly decreased concentrations of non-esterified fatty acids in fetal growth restriction placentas

Correlations between placenta lipid concentrations and clinical characteristics

• Many PC molecules measured in placenta homogenate directly correlated with MCA PI
  • Almost all PCs containing arachidonic acid
  • Several PCs containing DHA

Discussion and conclusion: fetal growth restricted pregnancies have altered lipid profiles in cord blood, abnormal Doppler

Study authors found the analyzed fetal growth restriction infants had distinctly different lipid profiles in cord blood than those small for gestational age. It is the first known study exploring explicit relationships between fetoplacental lipid concentrations and specific ultrasound Doppler assessments in fetal growth restriction.

While the sample size was small, key findings demonstrated fetal growth restricted pregnancies correlated with abnormal Doppler flow indices of fetal vessels:

• Elevated cord plasma triglycerides, non-esterified LCPUFAs, EETs
• Reduced cord plasma DHA-LPC

These findings overall suggest that the worsening placental vascular resistance and progression to redistribution of fetal blood flow that occurs in severe fetal growth restriction influences intrauterine lipid metabolism. It is suspected to be fetal lipo-protective strategies in response to hypoxic in utero environment that ultimately could impact LCPUFA delivery to brain.

Future studies will help further define lipid signaling pathways directing synthesis/transport of specific lipid types in fetal growth restriction, assess changes in LCPUFA delivery to the brain, and determine subsequent impact on neurodevelopment.