Interpretation
We analyzed total 25(OH)D (25(OH)D2 +
25(OH)D3). There are different metabolites of vitamin D,
all with various stability and biological activity, mainly explained by
the affinity to the vitamin D receptor (1). Although new arrays for
measuring the different vitamin D metabolites, the international
recommendation is still to measure the cumulative level by quantifying
the amount of 25(OH)D (1). Total 25(OH)D has a long half-life-time
giving only minor variations within short periods, and it shows a
significant response to supplementation intake (increased
25(OH)D2,) but mainly to dermal vitamin production
(increase 25(OH)D3) (11). Interestingly, genetic factors
are shown to play a role in the uptake of 25(OH)D2 why
it is speculated if some require a higher supplementation dose than
others, but when it comes to transferring to the fetus, Novakovic et
al., concludes that maternal circulation 25(OH)D overrides genetic
factors (12). Due to the relatively low percentage of patients with
documented supplementation, we could not draw any conclusions except
that supplementation in general increases the maternal 25(OH)D level. In
contrast BMI, nationally, education, daily exposure to sunlight, or
diabetes did not significantly influence. How to optimize
supplementation is a subject for future research within personalized
medicine and big data analytics.
Some of our participants received a high dose of weekly vitamin D. The
Vitamin D supplementation could be as high as 20.000 IU/week plus 800 IU
daily from the prenatal vitamin tablets, making the accumulated dose
25.600 IU/week or 3657 IU/day. The highest dose of supplementation
evaluated during pregnancy is 4000 IU/day; a higher amount is thought to
cause fetal hypercalcemia (13). We had two patients with individualized
vitamin D supplementation; one had 8071 IU/day and the other 5085
IU/day, but none of the newborns had hypercalcemia (results not shown).
From the questionnaire, we know that 98% of the enrolled women were
well aware of the importance of supplementation, assuming most were
taking vitamin D without specifying how much. Recently, Izzeldin et al.
described a high incidence of 25OH)D levels <25nmol/L in
pregnant women in the United Arab Emirates (69%), whereas in our study
is was 28% (9). The time spent outside, the analysis method or genetic
factors cannot explain the difference (approximately 2% of women spent
more than 30 minutes outside per day, the same laboratory used, the same
population). In their study, 12% understood the importance of vitamin D
and enrolling in the second trimester theoretically before the first
antenatal care visit and discussion of supplementation; many of the
ladies could be deficient at enrollment. All the consultants and
specialist (n=17) in the Obstetrical/Gynecology department at our
hospital answered the questionnaire before study start. Within the
collegium there was no consensus on how to screen, treat or follow-up
the level of 25(OH)D (data not shown). This highlights the need to
implement a straightforward guideline where early screening for vitamin
D deficiency, women’s education, and how to give supplements are
accurate.
To avoid newborn vitamin D deficiency (defined as <30nmol/L)
it is suggested that maternal levels have to be >50 nmol/l
(8). Results from our study contradict this statement. With maternal
levels <50nmol/L no newborn was born with levels under
40.5nmol/L. Only if the mother had levels <23nmol/L was a risk
for deficiency in the newborn.
From numerous randomized trials, it is known that cord blood 25(OH)D
increases after supplementation during pregnancy, although an increase
does not consistently follow an equal rise in the mother (14). We
speculated if our result was due to the timing of maternal 25(OH)D
measurement. We could not explain the higher cord blood level by the
placenta weight, cord blood hematocrit, or mode of delivery (15). Out of
40 studies, Saraf et al. found only three studies describing a negative
ratio between maternal and fetal blood (10). One was analyzing
1,25-hydroxyvitamin D making a comparison to our study futile. The other
two studies were small but with designs very similar to ours i.e.,
maternal/fetal measurements close to each other (12,16). There is
evidence for fluctuation of the different vitamin D metabolites during
pregnancy. Fluctuation and months between maternal and newborn 25(OH)D
measurement, typical for most studies, interprets a correlation as
troublesome.
Compared to other studies, we successfully obtained a high number of
paired maternal and umbilical cord blood 25(OH)D samples within a
specific and narrow time frame. The correlation between maternal and
fetal levels was strongly correlated and independent of delivery mode
and maternal characteristics. We were not able to show any clinical
difference in the correlation over the range of different maternal
levels as shown by Wegienka et al. and Rabbani et al. Comparison between
methods showed that Wegienka et al. recruited patients throughout the
whole third trimester and also included 25(OH)D levels from the second
trimester. In Rabbian’s study, only 19% had received supplements before
blood sampling (7,17).
The evidence for an association between low 25(OH)D in the mother and
complications during pregnancy such as obesity, diabetes, preterm
rupture of the membranes, and dystocia are for discussion. Published
results are based on inhomogeneous observation studies, commonly without
specifying the timing for sampling (7–9). Although this study was not
an RCT we did not add evidence for an association between vitamin D
deficiency and complications in pregnancy or delivery.
Strenths : The study was conducted in a high endemic region and
with a high number of paired maternal and umbilical blood samples taking
within a specific and narrow time frame. Analysis of 25(OH)D was done
directly after sampling. Data was not retrieved from a register but
directly from the EMR, avoiding methodological errors.
Weakness : Nearly 50% of the women were un-booked, i.e., they had
no previous antenatal care visits in our hospital, implying that
specific antenatal data was missing. Due to hemolysis of the blood, it
was impossible to get the results of 25(OH)D in 66 cases.