To the best of our knowledge, this is the first study to examine the association between VitD intake before pregnancy and adverse obstetric outcomes based on the use of ART, using the largest Japanese birth cohort dataset. First, we found that the median (interquartile range) pre-pregnancy daily VitD intake among Japanese women was 4.3 (2.6–6.7) μg/day. Second, we found a relationship between basic maternal characteristics and daily VitD intake before pregnancy. The lowest daily VitD-intake group tended to be socioeconomically disadvantaged, i.e., maternal age < 20 years, smoking during pregnancy, lower maternal education level, and lower annual household income. Conversely, daily calorie intake increased along with daily VitD intake. Third, we found that excessive daily VitD intake could inversely increase some perinatal outcomes. Among all participants, the risk of SGA increased along with the daily VitD intake category. When we focused on women conceived by ART, although there was no dose-dependent relationship, the highest VitD-intake group (Q5) was associated with PTB at < 37 weeks, considering the middle VitD-intake group (Q3) as a reference.
VitD deficiency is a public concern worldwide. However, VitD is a fat-soluble vitamin and may accumulate in the body tissues, leading to toxicity. Therefore, we examined the association between higher VitD intake before pregnancy and obstetric outcomes; this is the first report which shows the adverse outcomes of higher pre-pregnancy VitD intake in women using ART.
VitD has important functional biological implications related to calcium, glucose, immune homeostasis, and anti-inflammation [20,21,22,23]. Most prior studies have concentrated on a deficiency in daily VitD intake and its association with adverse maternal and fetal outcomes, such as gestational diabetes mellitus, preeclampsia (a symptom of HDP, SGA, and PTB), and recurrent miscarriage . VitD supplementation is easily administered without apparent serious adverse events, while VitD deficiency often occurs among pregnant women. Therefore, several studies have examined how VitD supplementation during pregnancy improves obstetric outcomes [25,26,27]. Although numerous studies have suggested the benefits of VitD for fertility, some have indicated that excess VitD may have detrimental effects on fertility . Anifandis et al.  reported that VitD levels in the follicular fluid are negatively correlated with embryo quality while higher values of VitD are associated with a lower tendency of achieving pregnancy; further, women with overt hypervitaminosis D showed poor IVF outcomes . There is conflicting evidence regarding VitD supplementation and PTB. A recent Cochrane Database Systematic review reported that VitD supplementation may be associated with insignificant or no difference in the risk of PTB at < 37 weeks compared to no intervention or placebo (risk ratio: 0.66, 95% CI: 0.34–1.30; 7 trials, 1640 women, low-certainty evidence) . Conversely, a potential inverse association between maternal VitD status and PTB at < 37 weeks of gestation has been demonstrated , which was confirmed by our analysis. Inconsistent with the findings of the Cochrane Database Systematic review, our study showed that higher VitD intake was associated with PTB, especially among ART pregnancies. The mechanisms underlying the increased PTB risk induced by a higher VitD intake remain unclear and speculative. PTB has the same endpoint, consisting of two clinical subtypes—spontaneous PTB, mainly induced by inflammation, and medically-indicated PTB, encountered in cases of SGA or HDP . Higher VitD intake was not associated with either SGA or HDP among ART pregnancies; thus, we considered that the increased risk of PTB among ART pregnancies may be attributed to spontaneous PTB, associated with immune system functioning and inflammation.
Here, the median (interquartile range) pre-pregnancy VitD intake among all participants was 4.3 (2.6–6.7) μg/day. In Japan, the Ministry of Health, Labour and Welfare conducted the National Nutrition and Health survey and reported that the median daily VitD intake among women of 20–49 years was 2.3–2.4 μg/day (number of participants, 823) . An interest in preconception health has recently developed because preconception status markedly influences pregnancy outcomes and the long-term health of both mother and child . Regarding preconception care, appropriate diet counseling may motivate changes in food-intake behavior during pregnancy , particularly among women who wish to receive sterility counsel because they have times to consider preconception care . However, no UL exists for pregnant women, and our study indicated that in women who expect to conceive, a higher VitD intake before pregnancy (8.6–12.8 μg/day) may be associated with a shorter gestation period. Therefore, new recommendations regarding VitD intake before pregnancy are required to improve obstetric outcomes.
The major strength of this study is the utilization of data from a large-scale birth cohort study conducted by the Japanese government, with meticulous attention to data collection. Furthermore, this study is considered representative of the general pregnant population in Japan . Additionally, we included a large number of pregnancies achieved either with or without ART. Although a randomized controlled intervention trial is considered a better study design, it is impossible to conduct a long-term controlled trial examining overall dietary intake. Our results were not derived from a randomized controlled study; nevertheless, the large-scale nature of this cohort study allows for the evaluation of potential associations between adverse obstetric outcomes and preconception behaviors .
This study has some limitations. First, although we accounted for a few confounding factors, largely covering the questionnaires, other unknown factors may have affected the occurrence of PTB or SGA. Second, subjects were not stratified by the use of specific ART methods such as IVF and/or ICSI or the use of cryopreserved, frozen, or blastocyst embryo transfer. The information for ART also does not include homologous or heterologous. Third, the FFQ used in this study included dietary information for 1 year before pregnancy, but most questions were completed within the first trimester; therefore, a recall bias related to morning sickness may exist. Fourth, the FFQ referred particularly to Japanese alimentary habits and focused on Japanese women. Therefore, our results may not be generalizable to populations of other ethnicities. Fifth, we did not measure serum 25-hydroxy VitD concentrations, which would reflect total VitD in the maternal blood. Additionally, no assessment of VitD intake during pregnancy was performed, which is considered to confer benefits to obstetric outcomes. The absence of this data weakens the argument of an association between higher VitD intake in pregnancy and the subsequent obstetric outcomes. Finally, we did not focus on the effect of daily VitD intake before pregnancy on overall reproductive outcomes because JECS mainly included women who gave live birth.
Growing evidence has suggested the potential advantages of VitD supplementation during pregnancy. Therefore, the significance of sufficient preconception daily VitD intake has been established; however, we indicated that excess VitD intake before pregnancy may affect perinatal outcomes, particularly in women using ART. Women who expect to conceive by ART have more opportunities to undergo preconception care. Both benefits and accumulated toxicity effects of VitD should be considered because it is a fat-soluble vitamin.
Although sufficient daily VitD intake is essential, the results of this study may provide potential harmful effects of excessive intake of daily VitD. The effect of preconception daily VitD intake on obstetric outcomes could depend on the method of conception. We hope that this study will form the basis for appropriate, personalized counseling as a form of preconceptional care for those who will receive ART.