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.