Serum Vitamin D Concentrations, Time to Pregnancy, and Pregnancy Outcomes among Preconception Couples: A Cohort Study in Shanghai, China
Nutrients 2022, 14(15), 3058; https://doi.org/10.3390/nu14153058
by Yu Zhang 1,2ORCID,Anne Marie Z. Jukic 3,Heqing Song 1,Lifeng Zhang 4,Fengyun Yang 4,Shoule Wu 4,Dongxiao Yin 4 and Hong Jiang 1,*
1 School of Public Health, National Health Commission Key Laboratory of Health Technology Assessment, Fudan University, Shanghai 200032, China
2 Vital Statistics Department, Songjiang District Center for Disease Control and Prevention, Shanghai 201600, China
3 Epidemiology Branch, National Institute of Environmental Health Sciences, Durham, NC 27709, USA
4 Shanghai Jiading Maternal and Child Health Care Hospital, Shanghai 201812, China
Background: The role of vitamin D in reproductive health is still unclear. This study aimed to assess the effect of serum 25-hydroxyvitamin D (25(OH)D), among preconception couples, on fecundity, and the associations between 25(OH)D concentrations before and during pregnancy, and pregnancy outcomes.
Methods: 200 preconception couples attempting to conceive were recruited and were followed-up until childbirth. Time to pregnancy was collected via telephone every two months or obtained via a questionnaire during pregnancy. Blood samples were collected to measure serum 25(OH)D levels from both partners at enrollment and from women during the second and third trimester of pregnancy.
Results: Couples had higher conception rates within six months (adjusted odds ratio (aOR): 3.72, 95% CI: 1.16, 11.9) and reduced time to pregnancy (adjusted fecundability ratio (aFR): 1.50, 95% CI: 1.01, 2.23) if male partners had sufficient 25(OH)D compared with insufficient 25(OH)D.
Compared to pregnant women with insufficient 25(OH)D in the third trimester of pregnancy, sufficient 25(OH)D was associated with
- reduced odds of anemia (OR: 0.22, 95% CI: 0.06, 0.82),
- longer gestational age (β: 0.53, 95% CI: 0.04, 1.01) and
- newborns’ higher ponderal index (β: 0.10, 95% CI: 0.01, 0.19).
Conclusions: Sufficient serum 25(OH)D levels among preconception men or during pregnancy were associated with better reproductive health.
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To our knowledge, this is one of few studies in China that has prospectively examined the impacts of serum 25(OH)D levels on fecundity and pregnancy outcomes starting at preconception. Our findings suggest vitamin D deficiency and insufficiency were common among preconception couples. Compared with insufficient 25(OH)D (<30 ng/mL), sufficient 25(OH)D (>30 ng/mL) among male partners was associated with a higher rate of conception within six months and with shorter TTP. No association was found between serum 25(OH)D levels of preconception women and either the conception rate within six months of follow-up or TTP duration. Further, pregnant women with a high 25(OH)D level (>30 ng/mL) in the third trimester had increased gestational age at delivery, increased neonatal PI, and reduced risk of gestational anemia.
In this study, there was no association between serum 25(OH)D concentrations in preconception women and conception, which is consistent with one previous study among 203 healthy Danish women . However, three other studies have reported that higher 25(OH)D was associated with increased conception rates. A study of 132 healthy women in the northeast of the US found that women with a 25(OH)D at least 50 nmol/L equivalent to 20 ng/mL had three times the odds of clinical pregnancy within six months . Another study, including 1191 women with a history of pregnancy loss in the USA, reported an increased conception rate with higher 25(OH)D concentrations (aOR: 1.10, 95% CI: 1.01~1.20), but the study also found no association between preconception vitamin D and TTP, which is consistent with our findings . Finally, a recent study of 522 fertile women from central North Carolina found that compared to women with a 25(OH)D of 30-40 ng/mL, women with at least 50 ng/mL had an estimated 35% increase in fecundability (FR: 1.35, 95% CI 0.95-1.91), and women below 20 ng/mL had an estimated 45% reduction in fecundability (FR 0.55, 95% CI 0.23, 1.32). Across three categories (25(OH)D of <20 ng/mL, 30-40 ng/mL and >50 ng/mL), the probability of taking longer than 6 months to conceive was 51%, 28% and 15%, respectively . Animal models and in vitro studies have suggested that low 25(OH)D concentrations were associated with impaired fertility [22,23,43-45], while the underlying mechanism of this association remains unclear. Fertilization can be influenced by 1,25(OH)2D-VDR mediated nongenomic activity. Besides uterine receptivity and embryonic implantation, HOXA10 expression was upregulated by active vitamin D in an in vitro study of human endometrium, which might also explain the observed associations between vitamin D and fecundity [27,46]. The possible reasons to explain the differences between our study and other studies might be the sample size, vitamin D cutoffs, ethnicity of the study subjects, the study design, and the generally low levels of 25(OH)D in our population, which limited our ability to observe associations at higher 25(OH)D levels. Given the relative paucity of data in this area, more studies of multiple centers with larger sample sizes are needed to explore and confirm the associations between vitamin D and fecundity in the future.
Our results indicated men with a higher percentage of normal morphology sperm were more likely to have higher 25(OH)D levels. Semen quality analysis is an important method to evaluate male fertility. Currently, the effect of vitamin deficiency on semen quality remains controversial. In a cross-sectional study, men with vitamin D deficiency (<25 nmol/L) had a lower proportion of motile, progressive motile and normal morphology sperm (p < 0.05) compared with men with high vitamin D concentrations above 75 nmol/L . An animal study reported that fertility of rats was reduced by 73% in litters from vitamin D deficient male inseminations when compared to female rats inseminated by vitamin D replete males . Our study is consistent with these findings: vitamin D may play a role in male fertility.
Very few studies have included preconception men in examining vitamin D concentration and fecundity. In our study, the positive association was found between sufficient 25(OH)D concentrations among preconception men and time to pregnancy. An observational study conducted among 102 infertile couples found that the conception rate was significantly higher among male partners with normal vitamin D serum level (>30 ng/mL) compared with low vitamin D serum level (<30 ng/mL) . Some studies have suggested the possible mechanism that actives vitamin D could improve sperm-egg binding by increasing intracellular concentrations of calcium, and therefore increased acrosine activity which facilitates fertilization [50,51]. However, randomized clinical trials are needed to further determine whether systemic changes in vitamin D metabolites can influence men's reproduction.
Our finding that vitamin D sufficiency in the third trimester of pregnancy was associated with a lower rate of gestational anemia agrees with several prior studies, which suggests that maternal vitamin D deficiency in pregnancy may play a role in gestational anemia [18,52]. There are several possible mechanisms to explain the relationship between vitamin D deficiency and anemia. Vitamin D deficiency may upregulate hepddin—an iron-regulating peptide hormone made in the liver , which decreases hemoglobin concentrations and may contribute to anemia . The transcriptional suppression of hep- cidin gene (HAMP) expression mediated by 1,25-dihydroxyvitamin D binding to the VDR can cause the lower levels in hepcidin mRNA . Therefore, lower vitamin D levels were associated with higher hepcidin levels, which may reduce the expression of iron transporters in cell membranes, and thus restrict iron transport.
In the current study, vitamin D levels in the third trimester of pregnancy were associated with gestational age at delivery. Our results are consistent with several previous studies. For example, Morley et al. reported that gestational length was 0.7 week shorter (p < 0.05) in mothers with low vitamin D levels vs. mothers with higher vitamin D levels . In a multi-ethnic cohort study, pregnant women with higher vitamin D levels (>20 ng/mL) were reported to have a longer gestational age than women with lower vitamin D levels (<20 ng/mL) . However, there were also studies demonstrating a null relationship between vitamin D level and gestational age of delivery .
Our present study showed 25(OH)D sufficiency (>30 ng/mL) in the third trimester of pregnancy was associated with increased neonatal PI. While several systematic reviews suggested that maternal vitamin D status had no effect on offspring birth length [59,60], there were some studies displaying vitamin D deficiency of pregnant women might have a role on reduced birth weight [13,61]. PI is a more reasonable indicator reflecting physical development and adiposity of infant than length and weight. VDR in placenta plays an important role in pregnancy and maternal VDR gene polymorphism which may affect birth weight . Interestingly, a recent study proposed that maternal vitamin D status during pregnancy may be a significant determinant of the off-spring's telomere length, which is positively correlated with neonatal weight .
Our study was one of few studies examining both preconception women and men with respect to vitamin D and fecundity. The cohort design provided the opportunity to estimate the casual effect of vitamin D on the probability of pregnancy and pregnancy outcomes. The positive association between sufficient vitamin D among preconception men and the increased rate of conception joins a growing body of evidence supporting the importance of preconception vitamin D among fertile couples seeking natural conception, and it provides evidence for updating and improving pre-pregnancy healthcare guidelines. However, we had a relatively small sample size for our analysis of PTB and LBW. In addition, our study only included couples who had a successful pregnancy and live birth. About half of the TTP data in this study were acquired retrospectively during pregnancy, which might lead to misclassification. Moreover, we used 30 ng/mL as sufficiency cutoff point according to the Endocrine Society guidelines . However, it is needed to ascertain the associations between vitamin D and reproductive health outcomes using different cutoff points since there was a debate on whether guidelines derived from studies of North American participants are applicable to participants in other human populations, such as Asian populations.
Vitamin D deficiency and insufficiency were common among preconception couples. Couples whose male partners had sufficient 25(OH)D (>30 ng/mL) had a higher rate of conception within six months and a shorter TTP. Women with sufficient 25(OH)D levels during the third trimester of pregnancy had a lower rate of gestational anemia, a later gestational age at delivery, and their infants had an increased neonatal PI. This study suggested that sufficient male 25(OH)D concentrations before conception might have a positive effect on couple's fecundity, while female 25(OH)D levels were not associated with fecundity. More studies with a larger sample size, a broad distribution of 25(OH)D levels, and both male and female partners, are needed to explore and confirm the associations between vitamin D and fecundity and pregnancy outcomes in the future.
VitaminDWiki - Vitamin D greatly improves Fertility
- Vitamin D is needed for human fertility – goal is 50 ng – Sept 2018
- Live birth 1.7 X more likely after IVF if good level of vitamin D – meta-analysis Aug 2020
- If diagnosed infertile, more likely to have live birth if Vitamin D fortification – Feb 2020
- Preconception vitamin D is great - every extra 10 ng associated with 10 percent more likely to have live birth – Aug 2018
- In-vitro Fertilization costs at least 10,000 dollars, Vitamin D costs 5 dollars
- Women with more than minimum vitamin D were 3.4 X more likely to achieve pregnancy and 1.6 X more likely to have live births – June 2017
- Assisted Reproduction – 5 studies concluded vitamin D repletion helps – Review March 2015
- Pregnancy success increased 30 percent if sunny (or vitamin D) one month earlier – June 2015
- IVF 4X more successful for white women with lots of vitamin D – many studies
Increased male Vitamin D increases fertility
- Conception was 3.7X more likely if the male had a good level of Vitamin D – July 2022
- Far better sperm in fertility clinic if more than 30 ng of Vitamin D - June 2022
- Fertility (sperm) associated with vitamin D – meta-analysis Sept 2019
- Infertility - 71 percent of the time of BOTH partners had less than 20 ng of Vitamin D – Aug 2017
- Birth rates doubled with Vitamin D - 300,000 for infertile men – RCT Nov 2017
- Male fertility 4 X higher if high Vitamin D – Nov 2015
- Vitamin D somewhat assists reproduction – both the mother and the father – May 2014
- Male fertility is improved in many ways by vitamin D – Jan 2014
Decreased Fertility if decreased Vitamin D Receptor
- Unexplained infertility 4X more likely if poor vitamin D receptor – Dec 2020
- Male Infertility is associated with poor Vitamin D Receptor – July 2021