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In a 2021 double-blind randomized trial which enrolled pregnant women in Northern Ireland, the primary outcome was the effect of vitamin D supplementation on levels of both maternal and umbilical 25-hydroxyvitamin D ([25(OH)D]), as well as the secondary goal of evaluating any impact of obesity. Two hundred and forty women (166 completed the study) were recruited to receive either 400 IU or 800 IU vitamin D (along with a multivitamin) starting in the 12th week of gestation and continued throughout the pregnancy. An approximately equal number of women that were normal weight, overweight, or obese comprised both groups. It has previously been established that obesity increases the risk for vitamin D insufficiency during pregnancy, even when dietary intake of vitamin D is higher than compared to women with normal weight.
There were several important take-aways from this study. Using 50 nmol/L [25(OH)D] as a benchmark for sufficiency, 45% of women entering the study had levels below this threshold, including approximately half of the women that were supplementing with vitamin D prior to the study even beginning. Among women who started pregnancy with a sufficient [25(OH)D] status, supplementing with 400 IU throughout pregnancy was enough to maintain sufficiency; however, among women below this threshold at the beginning of the study, 400 IU was not adequate to raise the mean [25(OH)D] to a sufficient level, and 45% of women in this group were considered insufficient by week 36.
Perhaps at least as important, even among women that started their pregnancy with a sufficient status, 400 IU was not enough to adequately raise the mean umbilical cord [25(OH)D] (mean in this group was 36.8 ± 14.7 nmol/L). 800 IU was a high enough dose to raise both mean maternal and umbilical levels to sufficiency, even among women starting pregnancy with insufficient levels, though it is important to note that by 36 weeks, the [25(OH)D] of just under 10% of women was still classified as insufficient even when receiving 800 IU.
Finally, the influence of obesity on both maternal and umbilical [25(OH)] was quite important, especially considering pre-pregnancy obesity is on the rise in 49/50 states, and in 2019 affected 29% of women in the US. First, 400 IU was an inadequate dose among women with obesity; 20% of women with obesity receiving 400 IU had insufficient [25(OH)D] by 36 weeks, as did 17.5% receiving 800 IU. Indeed, even among women with obesity that had sufficient levels prior to pregnancy, the mean dropped into the insufficient range, despite supplementing with 800 IU. Additionally, among women with obesity that began pregnancy with insufficient status, the mean umbilical cord status was deficient (<25 nmol/L [25(OH)D]) regardless of the vitamin D dose. Furthermore, in this group of women, umbilical cord levels remained low if their pregnancy began with an insufficient [25(OH)D], even if the mother’s 36 week [25(OH)D] was sufficient, a phenomenon not observed in normal weight or overweight pregnant women, suggesting poor placental transfer of vitamin D among women with obesity.
In summary, 400 IU was only likely to be sufficient among non-obese pre-pregnant women who began pregnancy with adequate [25(OH)D] levels, and higher doses were needed for those starting out with insufficient levels. Among women with obesity, even levels as high as 800 IU may not be adequate to prevent umbilical cord deficiency, especially if starting the pregnancy at low levels, and even if maternal levels appear okay.
It’s fairly well-established that low vitamin D levels have consequences for both the pregnant woman, including pre-eclampsia and gestational diabetes, as well as for the offspring, including low birth weight (small gestational age) and pre-term birth, and that vitamin D is needed for numerous biological actions in the fetus, including skeletal development and tooth enamel formation as well as immune function and surveillance. Yet the optimal maternal and umbilical [25(OH)D], as well as the optimal dose of vitamin D during pregnancy are not as clear cut. In a previously conducted randomized and double-blinded trial also done in Ireland, a total maternal vitamin D intake of 1200 IU (a combination of supplement and food) was predicted to keep 97.5% of women at sufficient [25(OH)D] levels throughout pregnancy, as well as 95–99% of umbilical cord sera above a 25-30 nmol/L threshold. However, this study was not designed to capture the influence of obesity and may not have been powered to do so. All of the women were also white, which does not accurately reflect vitamin D status among other ethnicities.
In a 2018 JAMA Pediatrics systematic review of 24 clinical trials, the authors concluded that a dose of 2000 IU or less was associated with risk reduction for a number of conditions, including fetal/neonatal mortality, though a dose higher than this was not. However, this review included multiple studies using very high doses administered infrequently (e.g., 1 dose of 200,000 IU), which typically do not show the benefit seen with more frequent lower doses. Also, the caveats related to body mass index and levels pre-pregnancy may be lost in these larger analyses. In addition to vitamin D, levels of micronutrients such as folic acid and B12 have also been inversely linked with pre-pregnancy body mass index. It’s also worth noting that adherence to a Mediterranean diet has been associated with higher []25(OH)D] levels, possibly via antioxidant or anti-inflammatory pathways, and has been shown to reduce the risk for gestational diabetes among pregnant women with metabolic risk factors.
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