DISCUSSION
4.1 Main
findings
This study shows a 10%/day higher maternal UPF intake is positively
associated with first-trimester density of vascular branching
(bifurcation points: β = 0.465 √n, p = 0.006). The intake
of carbohydrates, in particular of mono-and di-saccharides, is
associated with increased absolute morphologic development of the
first-trimester utero-placental vasculature, but not with density of
vascular branching. We established positive associations between
adherence to a Snack dietary pattern and absolute morphologic
development of the utero-placental vasculature in model 2, but no clear
associations in model 3. A graphic summary of the results is depicted in
Figure 4.
4.2 Strengths and
Limitations
Strengths of our study are the use of validated FFQ’s to study
periconceptional nutritional intake, application of the validated
Goldberg cut-off to exclude cases with unreliable nutritional intake and
the use of EPIC project-based food groups to categorize food items for
the identification of the dietary patterns 24-26.
The prospective observational study design allowed us to collect a
comprehensive set of patient characteristics, which we used as
covariates in advanced statistical models to minimize the effect of
confounding bias. Although we cannot exclude the possibility of residual
bias from any unknown factors, the direction of the effect estimates is
similar in all three models. Therefore we consider it unlikely our
findings result from residual confounding.
We used a unique longitudinal data collection of power Doppler
ultrasounds in the first trimester of pregnancy to perform validated
uPVV measurements (ICC above 0.80 and relative differences of less than
20%) 19 and subsequently generate the uPVS, our
imaging markers of utero-placental vascular development20.
Recruitment from an academic hospital might affect the generalizability
of our results. Although our study population contains a relatively high
number of IVF-ICSI pregnancies and participants have a higher risk of
developing pregnancy complications 21, we believe it
is unlikely the direction of the associations will be different in the
general population.
We performed multiple statistical analysis, which raises some concern
about multiple testing. However, previously uPVV and uPVS
characteristics were highly correlated and are inversely correlated with
the density of vascular branching20. Therefore, the
positive correlations between the effect estimates of uPVV and uPVS
characteristics and the inverse correlation with density of vascular
branching found in the present study can be interpreted as internal
validation.
4.3 Interpretation (in light of other
evidence)
4.3.1 Ultra-processed foods
So far, no studies have investigated associations between the
consumption of UPF and placental development. High UPF intake is
associated with increased total energy intake, an overall unhealthy
dietary pattern and an increased risk of obesity 15,
29-31. UPF intake is negatively associated with embryonic growth and
most studies on the effect of UPF-rich diets on birthweight suggests
high UPF intake is associated with lower birth weight14, 32-35. In the present study, UPF is positively
associated with first-trimester density of vascular branching, which has
previously been associated with decreased embryonic and foetal growth
and lower birth weight percentiles36, 37. Associations
with UPF persist in model 3, which implies our findings are not solely
mediated by higher energy content in UPF. We propose a high UPF exposure
induces oxidative stress resulting in aberrant first-trimester vascular
development and a compensatory increased density of vascular branching.
This way the first-trimester utero-placental vascular development might
act as a mediator in the relation between periconceptional maternal
intake and pregnancy outcomes. This mechanism is substantiated by
previous research on associations between UPF intake, oxidative stress,
first-trimester placental development and prenatal growth21, 22, 38-42.
4.3.2
Carbohydrates
In our study, periconceptional maternal carbohydrate intake, more
specifically of mono-and disaccharides, is positively associated with
volumetric and absolute morphologic utero-placental vascular development
in the first trimester. Carbohydrates seem to affect a different aspect
of the utero-placental vascular development than UPF, which likely
results from the high heterogeneity of the type and amounts of
carbohydrates in UPF-rich foods.
During the first trimester, the placental microenvironment is hypoxic43. Rather than on oxidative phosphorylation, the
placenta relies on glycolysis for energy production, supported by the
rich supply of glucose from the endometrial glands 44.
With increased carbohydrate intake maternal serum glucose concentration
rises and subsequently the expression of glucose transporter 1 (GLUT1)
increases. GLUT1 is an important cargo molecule of extracellular
vesicles that augment decidualization, stimulate angiogenesis, and
modulate trophoblast differentiation in the endometrial stroma45. The physiological interplay between serum glucose
and placental development is substantiated by previous research
indicating an insufficient glucose metabolism during gestation results
in placental aberrations and foetal growth restriction (FGR)46-50.
4.3.3 Fats and
Proteins
Multiple studies suggest fatty acids to play a regulatory role in the
angiogenesis in tumours and in various organs, including the placenta51-55. The contradictory pro- and antiangiogenic
effects of individual PUFAs might explain why we did not find any
associations between the periconceptional intake of fatty acids and
utero-placental vascular development 51, 52.
Not much is known about dietary intake of proteins and placental
development. Recent studies suggest low-protein diet is associated with
placental morphologic disruption and foetal growth restriction and found
maternal protein intake positively associated with prenatal growth56, 57. Our findings suggest it is unlikely
associations between protein intake and prenatal growth are mediated by
utero-placental vascular development.
4.3.5 Dietary
patterns
The Snack dietary pattern in this study is characterized by excessive
consumption of food items with high carbohydrate content. This might
explain why we found a (borderline-) statistically significant positive
associations between adherence to the high snack pattern and
first-trimester density of vascular branching in model 2 similar to the
associations with carbohydrates. However, the snack dietary pattern also
includes food items with high energetic value but relatively low
carbohydrate content, like butter. The heterogeneity in the Snack
dietary pattern and the small sample size might explain why the positive
associations in model 3 were not statistically significant.
4.4
Implications
The intake of UPF seems to impair first-trimester utero-placental
vascular development. These findings are not substantiated by
associations with related macronutrients and dietary patterns as
increased maternal intake of carbohydrates, within healthy quantities,
seems to promote first-trimester utero-placental vascular development.
Associations between UPF intake and placental vascular development could
reflect the effects of ‘ultra-processing’ techniques in the food
industry, but likely result from a coinciding lack of micronutrients in
these food items.58, 59 UPF-rich diets are associated
with deficiencies in folate and vitamin B12, important micronutrients
involved in the 1-carbon metabolism. Derangements in the 1-carbon
metabolism are associated with hyperhomocysteinemia and oxidative
stress, which causes aberrant development of the utero-placental
vasculature, associated with placenta-related
complications.60