Abstract
Among primates, human neonates have the largest brains but also the highest proportion of body fat. If placental nutrient supply is limited, the fetus faces a dilemma: should resources be allocated to brain growth, or to fat deposition for use as a potential postnatal energy reserve? We hypothesised that resolving this dilemma operates at the level of umbilical blood distribution entering the fetal liver. In 381 uncomplicated pregnancies in third trimester, we measured blood flow perfusing the fetal liver, or bypassing it via the ductus venosus to supply the brain and heart using ultrasound techniques. Across the range of fetal growth and independent of the mother's adiposity and parity, greater liver blood flow was associated with greater offspring fat mass measured by dual-energy X-ray absorptiometry, both in the infant at birth (r = 0.43, P<0.001) and at age 4 years (r = 0.16, P = 0.02). In contrast, smaller placentas less able to meet fetal demand for essential nutrients were associated with a brain-sparing flow pattern (r = 0.17, p = 0.02). This flow pattern was also associated with a higher degree of shunting through ductus venosus (P = 0.04). We propose that humans evolved a developmental strategy to prioritize nutrient allocation for prenatal fat deposition when the supply of conditionally essential nutrients requiring hepatic inter-conversion is limited, switching resource allocation to favour the brain if the supply of essential nutrients is limited. Facilitated placental transfer mechanisms for glucose and other nutrients evolved in environments less affluent than those now prevalent in developed populations, and we propose that in circumstances of maternal adiposity and nutrient excess these mechanisms now also lead to prenatal fat deposition. Prenatal developmental influences play important roles in the human propensity to deposit fat.
Highlights
At birth the human fetus has the highest percentage of body fat [1] and the largest brain of any primate species [2]
middle cerebral artery pulsatility index (MCA pulsatility index (PI)) was lower in male than in female fetuses (P = 0.03) (Fig. 2A), and in those with smaller placenta weights (r = 0.17, P = 0.02) (Fig. 2B and Figure S1)
In this we hypothesise that the balance between fetal nutrient demand and materno-placental nutrient supply may alter the distribution of umbilical venous blood flow, Figure 3
Summary
At birth the human fetus has the highest percentage of body fat [1] and the largest brain of any primate species [2]. Under circumstances of reduced oxygenation or nutrition, a higher proportion of blood from the umbilical vein bypasses the liver and perfuses the head and neck of the fetus, prioritizing oxygen and nutrient delivery to the brain as part of the so-called ‘brain-sparing’ effect [6,7]. In growth-restricted human fetuses, such brain-sparing responses are associated with cerebral vasodilation (measured using Doppler ultrasound as a low pulsatility index in the middle cerebral artery [5]) and with greater ductus venosus shunting (Fig. 1) [6,7] It is not known whether such adaptive changes in brain and liver blood flow occur in normally growing fetuses, there are large variations in the proportion of placental blood perfusing or bypassing the liver in late gestation in such fetuses. As the balance between fetal nutrient demands and maternoplacental nutrient supply is influenced by fetal gender (greater demand in male fetuses, as they grow faster than female fetuses [11]), and placental size (reduced supply if the placenta is smaller [12,13]) we have examined fetal adaptive responses in relation to gender and placental weight, and determined relationships with adiposity at birth and at age 4 years
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