【Discussion】
Low
vitamin D status is a global epidemic affecting people of all ages. It
has attracted scholars of great interest in recent years. Although
vitamin D is important for musculoskeletal health, increasing data
suggest that vitamin D may also be important for fertility and pregnancy
outcomes[18]. The number of research on the
pleiotropic effects of vitamin D in pregnancy and the impact of low
vitamin D status on maternal and infant outcomes has been expanding.
The main role of vitamin D during pregnancy is to promote calcium
absorption and placental calcium transport. Existing evidence on
maternal 25(OH)D concentrations during pregnancy is inconsistent,
possibly due to small study samples, lack of adjustment for seasonal or
ethnic variation and cross-sectional
design[11].Some studies suggest that women are
more likely to suffer from vitamin D deficiency or insufficiency during
pregnancy and with a gradual decrease in the total amount of 25(OH)D
from the first trimester to term[19] because the
change of their hormone and metabolic conditions and the required
nutrients increase significantly[20]. A
meta-analysis carried out by Papapetrou, P. D.[21] reported no difference in the concentrations
of 25(OH)D before, either during or after pregnancy. It’s unclear
whether low vitamin D status is more frequent in pregnant women when
compared to same-aged nonpregnant women. Therefore, pregnancy may not
be a cause of low vitamin D status compared to nonpregnancy.
Risk
factors associated with low vitamin D status delineated by several
studies are: inadequate sun explore, low ambient UVR levels, physical
inactivity, low dietary vitamin D intake, no or low vitamin D
supplementation and medication[22].
Moreover, variations in skin color,
social and cultural habits concerning sun seeking behavior, diet, and
other factors are evident. However, there is no authoritative criteria
for appropriate vitamin D status in pregnancy. Different criteria have
been used for diagnosing vitamin D deficiency, but mostly referring to
50nmol/L and 75nmol/L. A high prevalence of vitamin D deficiency up to
62.34% was reported in South China[23]. Recent
evidence showed that pregnant women in Shanghai are generally deficient
in vitamin D, the results suggesting that 72.5% of the participants were
vitamin D deficient[24]. At present, the
classification standard for the determination of serum 25(OH)D
concentration recommended by the IOM is still an indicator commonly used
internationally to categorize vitamin D status in adults. A large
number of studies[6, 11, 25, 26]published in
recent years emphasize the relationship between low vitamin D status and
several adverse pregnancy outcomes such as PE, GDM, preterm birth, etc
according to IOM standard. Rostami et al[27] infer
the ideal level of vitamin D during pregnancy based on pregnancy
outcomes, they recommend a cutoff of 25(OH)D >37.5 nmol/L
for the prevention of adverse pregnancy outcomes.
In this study, vitamin D levels were
measured in Asian pregnant women in South China on a normal diet during
pregnancy. In contrast to many conclusions based on White British women
and Pakistani women[28], the study found no
significant association between low vitamin D status and adverse
pregnancy outcomes. The reasons may be as follows: 1) The current
vitamin D assessment is based on the
upper limit of vitamin D level that satisfies 97.5% of the population
to maintain normal bone health, instead of the “cut-off value” based
on pregnancy outcomes. 2)The efficiency of vitamin D utilization was
variable among people with different skin colors[11],3)Low
vitamin D might affect pregnancy in the long term after delivery,
consequently, women’s long-term outcomes and the development of children
should be given as much attention as the adverse outcomes associated
with vitamin D during pregnancy. These speculations still need to be
confirmed by more studies.
At present, vitamin D screening during pregnancy has been increasingly used as a routine antenatal examination, which leads to additional
vitamin D supplement distribution to pregnant women with low vitamin D
status. In fact, studies on the association of vitamin D and pregnancy
outcomes have not reached agreement. A Mendelian randomization study
found no strong evidence to support an effect of vitamin D status on
pregnancy related hypertensive disorders[29].
Observational studies have also not found that low vitamin D levels are
associated with postpartum hemorrhage and showed an inverse
relationship between vitamin D status and the occurrence of postpartum
hemorrhage which remains unexplained [18, 25].
Agarwal, S et al[2] reviewed plenty observational
and interventional studies, and they found that the role of vitamin D in
GDM remains inconclusive, and this critical review showed that several
observational studies reported an inverse relationship between vitamin D
status in early pregnancy and the risk of GDM, conversely, there were
also multiple studies failed to determine the role of vitamin D in the
prevention of GDM. Large-scale prospective studies are still needed to
assess the role of vitamin D in GDM. This prospective study demonstrated
that low vitamin D status is not associated with adverse pregnancy
outcomes, which was different from other
researches[8, 30, 31].In other words,
is low vitamin D status in pregnant
women really matters, should we give positive medical intervention
remains uncertain and requires further
confirmation. Most experts agree
that broad-based screening of serum 25(OH)D levels in the general
population or during pregnancy is unnecessary[32].
In addition, the issue of vitamin D supplementation during pregnancy
still needs to be further explored. Some high-quality RCT studies have
failed to prove that vitamin D supplementation during pregnancy can
reduce pregnancy complications and is beneficial to the development of
fetus[33-35]. In France and in Belgium, women are
not routinely supplemented with vitamin D before
pregnancy[17]. A review also questioned whether
vitamin D supplementation improved outcomes in osteoporosis
prevention[36].
Research concludes that different
populations in different regions
have not been unified, neither RCTs nor observational trials have
demonstrated that serum vitamin D levels are associated with pregnancy
outcomes, nor have vitamin D supplementation improved pregnancy
outcomes. This is because, on the
one hand, vitamin D “deficiency” or “insufficiency” diagnosed by the
IOM criteria is not necessarily applicable to all populations in all
regions of the world, and on the other hand, low vitamin D status may
not be correlated with most adverse outcomes.
It is important to clarify the meaning of IOM reference values for
vitamin D, as they are related to both human health and clinical
considerations. In fact, the use of “50nmol/L” and “30nmol/L” as a
cut-off value is based on misinterpretation and misapplication of the
IOM vitamin D reference values. The IOM developed these reference
values, referred to as Dietary Reference Intakes (DRIs), for a range of
nutrients. That is, the cause relationship of vitamin D and
musculoskeletal health outcomes was used to inform dietary vitamin D
requirements. Central to the DRI concept is the biologic reality that
the requirements for any nutrient vary from person to person, and are
usually normally distributed across the population. However, the exact
nutritional requirements of an individual cannot be known. A common
misconception is that the RDA functions as a “cut point” and that
almost the entire population must have a serum 25(OH)D level above
50nmol/L to achieve good bone health[32]. Note
that the values assume minimal to no sun.
Vitamin D levels largely depend on
exposure to the sun and are influenced by nutritional habits at only a
minimal level[11].The reality is that most (about
97.5%) of the population has a requirement of vitamin D 50nmol/L or
less[32]. Diagnosis of vitamin D “deficiency” or
“insufficiency” itself presents a challenge due to the “diagnostic
threshold” of vitamin D status in pregnancy cannot be equated with
“nutrient supply”. A systematic review and meta-analysis published
recent years [33] showed that, neither
intermittent nor daily standard doses of vitamin D alone were associated
with a reduced risk of fracture. Excessive concern about vitamin D
“deficiency” or “insufficiency” can adversely affect patient care,
including unnecessary vitamin D screening and supplementation,
as well as rising health care costs.
Low vitamin D status may not relate
to adverse pregnancy outcomes. However, the results bias caused by
research samples cannot be ruled out. The etiology of various maternal
and infant outcomes is complex and multifactorial, with many confounding
factors. Determining the relationship of vitamin D levels during
pregnancy requires further evaluation through large, multicenter,
randomized controlled clinical trials focusing on specific adverse
pregnancy outcomes.