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Current Recommended Vitamin D Prenatal Supplementation and Fetal

Growth
Results From the China-Anhui Birth Cohort Study

Rui-xue Tao; Deng-hon Meng; Jing-jing Li; Shi-lu Tong; Jia-hu Hao; Kun Huang; Fang-biao Tao; Peng Zhu

J Clin Endocrinol Metab. 2018;103(1):244-252.

Abstract and Introduction

Abstract

Context: Maternal vitamin D insufficiency has been associated with fetal growth restriction. However, the effect of maternal
vitamin D supplementation on fetal growth has not been confirmed.

Objective: To assess the effect of maternal vitamin D supplementation recommended by the Institute of Medicine (IOM) during
pregnancy on the neonatal vitamin D status and the risk of small for gestational age (SGA).

Design and Participants: As part of the China–Anhui Birth Cohort study, maternal sociodemographic characteristics, food intake,
lifestyle, information on vitamin D supplementation, and birth outcomes were prospectively collected. For participants, 600 IU/d of
vitamin D3 ,was routinely advised to take during pregnancy. Cord blood levels of 25-hydroxyvitamin D [25(OH)D], calcium, and
phosphorus were measured in 1491 neonates who were divided into three groups based on the duration of maternal vitamin D
supplementation during pregnancy.

Results: Mean cord blood concentrations of 25(OH)D were 3.5 nmol/L higher [95% confidence interval (CI), 0.8, 6.2] in neonates
(median, 37.9 nmol/L) whose mother took vitamin D supplementation for >2 months during pregnancy compared with those
(median, 34.3 nmol/L)whose mother did not take any supplement. These significant differences on cord blood concentrations of
25(OH)D occurred regardless of the season of birth. The adjusted risk of SGA in pregnant women with vitamin D supplementation
for >2 months was significantly decreased than that in women without any vitamin D supplementation (11.8% vs 6.9%; adjusted
odds ratio = 0.53; 95% CI, 0.32, 0.87).

Conclusions: The findings from China suggest that maternal vitamin D supplementation recommended by the IOM results in a
slight but significantly higher fetal level of 25(OH)D and improves fetal growth.

Introduction

Vitamin D deficiency is emerging as a significant public health problem worldwide in all populations,[1] including newborns,
children, adolescents, pregnant women, and the elderly. Studies of pregnant women have shown a high prevalence of maternal
deficiency (25-hydroxyvitamin D [25(OH)D] < 50 nmol/L) in the United States (37%),[2] the United Kingdom (49% to 75%),[3,4] and
China (70% to 80%).[5,6] It is noteworthy that fetal and newborn concentrations of 25(OH)D depend on and correlate with
maternal serum levels.[7,8] Thus, maternal levels of vitamin D during pregnancy determined the vitamin D status at birth and
during early life in offspring.[9]

Increasing evidence from observational studies[10–17] has identified the link between maternal vitamin D deficiency or
insufficiency and fetal growth restriction. A meta-analysis of an observational study reinforced the association between vitamin D
deficiency and the risk of small for gestational age (SGA).[18] Despite these findings, the translation to clinical practice has not
occurred. In China, most obstetricians are unaware of the vitamin D content in prenatal vitamins. Current evidence on maternal
vitamin D status and fetal growth restriction derives largely from observational studies, but small supplementation studies.
Understanding of the clinical importance and implications of maternal vitamin D supplement is limited.

A previous placebo-controlled randomized trial conducted >30 years ago demonstrated that maternal vitamin D supplementation
at a dose of 1000 IU/d in Asian women during the third trimester led to a nonsignificant reduction in the rate of SGA.[19] A
Cochrane Review[20] published in 2012 reported that data from three trials involving 463 women suggested that pregnant women
who receive vitamin D supplements less frequently had a baby with lower birth weight than those receiving no treatment or
placebo; statistical significance was borderline [relative risk, 0.48; 95% confidence interval (CI), 0.23, 1.01]. From these limited
data, the Cochrane Review concluded that there was insufficient evidence to evaluate the effects of vitamin D supplementation
during pregnancy.[20] Since then, few studies have addressed this issue and the results have been mixed.[7,21–23] The
controversial findings may be due to variations of study designs, including the gestational weeks, dose, season, and adherence of
maternal vitamin D supplementation as well as ethnicity of the study population.

A 2010 review of the vitamin D requirements by the Institute of Medicine (IOM) resulted in a revised recommended daily
allowance of 600 IU/d of vitamin D for women during pregnancy.[24] However, the effect of maternal vitamin D supplementation
with 600 IU/d on fetal growth has not been evaluated in China. In this study, we examined the effect of vitamin D supplementation
according to the new recommendation of the IOM during the second and third trimester in Chinese pregnant women on cord
blood levels of 25(OH)D, calcium, and phosphorus and the risk of SGA.

Subjects and Methods

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Study Populations and Design

As part of the China-Anhui Birth Cohort study,[25] this study was undertaken based on a prospective birth cohort including 2552
married pregnant women enrolled from January to September 2008 in Hefei (32°N latitude). Pregnant women who received
prenatal checkups in Hefei Maternal and Child Health Hospital were required to complete a structured questionnaire that included
sociodemographic characteristics and lifestyle. At birth, the newborn's anthropometric details and cord blood were collected by
study nurses. To remove potential confounding factors in possible maternal medical risks, the following exclusion criteria were
applied: stillbirth (n = 11), birth defect (n = 12), women with delivery before 32 weeks of gestation (n = 14), pregnancy with
assisted reproductive technology (n = 6), or multiple gestations (n = 48). We finally obtained full data, including cord blood from
1491 mother– infant pairs. The study was approved by the Ethics Committee of the Anhui Medical University, and informed
consent was obtained from each participant.

Maternal Vitamin D Supplementation

When participants first received prenatal checkups in obstetrics clinics, they were routinely advised to take 600 IU/d of vitamin D3
supplementation during the second and third trimesters. Pregnant women were requested to bring back used commercial vitamin
D bottles to receive guidance for the dose of supplementation at subsequent antenatal checkups. At the last visit before delivery,
each participant was invited to report the duration and dose of vitamin D supplementation. It was assessed with the question,
"How long have you taken vitamin D during pregnancy?" However, most pregnant women could not report the exact dose of
vitamin D supplementation. According to participants' reports on the commercial vitamin D supplementation, the dose ranged from
400 to 600 IU/d. For analytic purposes, the duration of vitamin D supplementation was categorized as follows: no use of vitamin D
(nonsupplemented group), using vitamin D for <2 months (supplement group A), and using vitamin D for >2 months (supplement
group B).

Cord Blood 25(OH)D, Calcium, and Phosphorus

After delivery, midwives immediately collected cord blood samples and anticoagulated them by using sodium heparin. Plasma
samples were centrifuged and promptly refrigerated at −4°C, within 12 hours, and transferred to −80°C freezers for long-term
storage. Concentrations of 25(OH)D were measured by using commercial radioimmunoassay kits (DiaSorin, Stillwater, MN), and
quantitative outcomes were obtained. Intra-assay and inter-assay coefficients of variation were 8.8% and 11.1%, respectively.
Plasma calcium and phosphorus were measured by standard auto analyzer methods (Beckman-AU680; Beckman Coulter, Brea,
CA). Cord blood concentrations of 25(OH)D were analyzed as a continuous variable and were categorized as <50 nmol/L
(deficiency) and ≥50 nmol/L,[26] as recommended by the Canadian Pediatric Society.[27]

SGA

The primary outcomes for this analysis were based on SGA defined as birth weight < the 10th percentile of distribution for
gestational age and on infant sex.[28] Birth weight was measured by study nurses at birth. The accuracy of scales used to
measure birth weight was checked using standard weights at the beginning of the study and every 3 months thereafter. The
gestational age (in completed weeks) was calculated based on the difference between the date of the last menstrual period and
the date of delivery, which were obtained from hospital records.

Covariates

The most important potential confounders were season of birth, prepregnancy body mass index (BMI), and maternal gestational
weight gain (GWG) because of their known associations with both plasma 25(OH)D levels[16] and fetal growth.[29] Other potential
confounding variables included maternal sociodemographic characteristics (age, education, and household income),
prepregnancy lifestyle (alcohol consumption and smoking), food intake frequency during pregnancy (milk and eggs), health status
(parity and complication of pregnancy), and birth outcomes (gestational weeks and infant sex), which were assessed through the
interview or the medical records. Season of birth was designated as winter (December, January, February), spring (March, April,
May), summer (June, July, August), or fall (September, October, November). Prepregnancy BMI was calculated on the basis of
the height routinely measured at the clinic visit and on the self-reported prepregnancy weight obtained at interview and were
divided into underweight (<18.5), normal weight (18.5 to 23.9), or overweight or obese (≥24.0).[30] The weight gain throughout
pregnancy was determined by the difference between the prepregnancy weight and the measured weight recorded at the last
prenatal visit before delivery, which was categorized as insufficient, normal, and excessive weight gain based on the
recommendation for maternal weight gain in Chinese women.[31] Complications of pregnancy included diabetes mellitus,
hypertension, abnormal heart function, glandula thyreoidea disease, intrahepatic cholestasis of pregnancy, and moderate and
severe anemia.

Statistical Analysis

The demographics and clinical characteristics of the study population were described according to maternal vitamin D
supplementation status. We tested for trends across maternal vitamin D supplementation status for each of the characteristics by
using linear regression or the Kruskal–Wallis test for continuous variables and Mantel–Haenszel χ 2 test or a nonparametric test
for trends based on the Wilcoxon– Mann–Whitney test for categorical variables. Differences in cord blood concentrations of
25(OH)D according to characteristics of the mother–infant were evaluated using linear regression models, and β coefficients and
95% CIs were generated.

We examined the differences in cord blood concentrations of 25(OH)D among three groups of maternal vitamin supplementation
using multiple linear models, and the nonsupplementation group was regarded as the reference. To reduce the influence of
covariates on plasma concentrations of 25(OH)D, we examined levels of 25(OH)D in four ways: (1) unadjusted, (2) adjusted for
season of birth, (3) additionally adjusted for prepregnancy BMI and GWG, and (4) additionally adjusted for maternal
sociodemographic characteristics (age, education, income), prepregnancy lifestyle (maternal alcohol consumption, father
smoking, and alcohol consumption), food intake during pregnancy (milk and eggs), health status (parity and complication of
pregnancy), and birth outcomes (gestational weeks and infant sex). The risks of neonatal vitamin D deficiency were assessed by
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using multiple logistic regression models after adjustment for confounders as described above, and the odds ratios (ORs) and
95% CIs were generated.

Seasonal patterns of 25(OH)D concentration in cord blood for neonates among three groups of maternal vitamin D
supplementation were assessed by linear regression models. Multiple logistic regression analysis was performed to determine the
effect of maternal vitamin D supplementation on the risk of subsequent SGA with adjustment for confounders. The effect of birth
seasons on the fetal growth was furtherly identified through stratification analysis. We also investigated the association of cord
blood 25(OH)D with calcium and phosphorus through using linear regression models. We performed all analyses by using SPSS
21.0.

Results

Attrition analyses showed that there were no differences between nonparticipants and participants in the distributions of
sociodemographic characteristics, health status, food intake, lifestyle, and birth outcomes.

The characteristics of the study population are shown in . Of 1491 mother–infant pairs in this analysis, 21.7% were not using any
vitamin D supplementation during pregnancy, 30.6% were using vitamin D supplementation for <2 months, and 47.7% were using
vitamin D supplementation for >2 months. Pregnant women with higher social economic status, primipara, and male infants
tended to have a longer duration of vitamin D supplementation. Increasing duration of maternal vitamin D supplementation was
significantly related with the higher intake frequency of eggs and milk, as well as more GWG, gestational weeks, and birth weight
(P < 0.05 for the trend). The mean cord blood concentration of 25(OH)D among 1491 newborns was 39.4 nmol/L (standard
deviation of 20.4), ranging from 6.1 to 119.6 nmol/L. Overall, 75.2% of neonates had 25(OH)D levels of <50 nmol/L, and only
24.8% had levels of ≥50 nmol/L. The mean cord blood concentration of 25(OH)D significantly increased across the three groups,
but there was no significant difference for the concentration of calcium and phosphorus among the three groups.

Table 1. Demographics and Clinical Characteristics of Study Population

Study Groups
Nonsupplement Supplement Group A Supplement Group B P for
Characteristics Group a (n = 323) b (n = 456) c (n = 712) Trend d
Sociodemographic characteristics        
Maternal age [mean (SD)], y 27.5 (4.2) 27.4 (3.7) 27.9 (3.3) 0.039
Maternal education ≥ 9y[n (%)] 202 (17.1) 360 (30.5) 619 (52.4) <0.001
Family monthly income ≥ 4000 41 (24.7) 48 (28.9) 77 (46.4) 0.079
RMB/yuan [n (%)]
Health status        
Prepregnancy BMI [mean (SD)] 20.3 (2.5) 20.2 (2.5) 20.0 (2.3) 0.319
Gestational weight gain [mean (SD)], 16.3 (5.1) 16.5 (4.8) 17.1 (4.7) 0.008
kg
Primipara [n (%)] 264 (81.7) 383 (84.0) 645 (90.6) <0.001
Complication of pregnancy [n (%)] e 53 (16.4) 79 (17.3) 94 (13.2) 0.101
Prepregnancy lifestyle f
Maternal alcohol consumption [n (%)] g 41 (12.7) 82 (18.0) 102 (14.3) 0.834
Paternal smoking [n (%)] h 70 (21.7) 112 (24.6) 154 (21.6) 0.932
Paternal alcohol consumption [n (%)] g 251 (77.7) 362 (79.4) 586 (82.3) 0.067
Food frequency during pregnancy        
Maternal egg intake > 3 times/wk [n 218 (67.5) 310 (68.0) 527 (74.0) 0.015
(%)]
Maternal milk intake > 3 times/wk [n 239 (74.0) 359 (78.7) 608 (85.4) <0.001
(%)]
Birth outcomes        
Male infant [n (%)] 186 (57.6) 252 (55.3) 353 (49.6) 0.010
Birth during summer or autumn [n (%)] 180 (55.7) 242 (53.1) 370 (52.0) 0.276
Gestational wk [mean (SD)], wk 38.7 (1.8) 38.8 (1.5) 39.0 (1.3) 0.001
Birth weight [mean (SD)], g 3333.1 (493.3) 3397.0 (479.4) 3400.3 (406.3) 0.043
25(OH)D [mean (SD)], nmol/L 36.9 (18.7) 39.0 (20.8) 40.8 (20.7) 0.004
Calcium [mean (SD)], mmol/L 0.170 (0.022) 0.170 (0.024) 0.170 (0.023) 0.635
Phosphorus [mean (SD)], mmol/L 1.54 (0.20) 1.54 (0.20) 1.54 (0.20) 0.580
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Abbreviation: SD, standard deviation.

a Nonsupplement group means pregnant women without any vitamin D supplementation.
b Supplement group A means pregnant women with vitamin D supplementation for <2 months during pregnancy.
c Supplement group B means pregnant women with vitamin D supplementation for >2 months during pregnancy.
dP for trend is based on linear regression or the Kruskal–Wallis test for continuous variables and the Mantel–Haenszel x2 test or a
nonparametric test for a trend based on the Wilcoxon–Mann–Whitney test for categorical variables.
e Complications of pregnancy included diabetes mellitus, hypertension, abnormal heart function, glandula thyreoidea disease,
intrahepatic cholestasis of pregnancy, and moderate and severe anemia.
f Prepregnancy lifestyle means lifestyle during up to 6 months before pregnancy.
g Alcohol consumption was defined as any alcohol consumption.
h Father's smoking was defined as more than six cigarettes daily.

The associations of plasma 25(OH)D concentration in cord blood with characteristics of mother–infant pairs in bivariate analyses
are shown in . Higher cord blood concentrations of 25(OH)D were observed in the pregnant women with insufficient GWG, absent
complication of pregnancy and prepregnancy alcohol consumption of husband, as well as delivery at spring, summer, or autumn.

Table 2. Differences in Cord Blood 25(OH)D according to Sociodemographic, Health Status, Food Intake, Lifestyle, and Birth
Outcomes

Characteristics N (%) Cord Blood 25(OH)D (nmol/L) P

Sociodemographic characteristics      
Maternal age, y      
20–24 252 (16.9) −0.16 (−3.03, 2.71) 0.914
25–29 870 (58.4) Ref.  
≥30 369 (24.7) 0.20 (−2.24, 2.64) 0.873
Maternal education, education years      
≤9 310 (20.8) −1.12 (3.67, −1.43) 0.388
>9 1181 (79.2) Ref.  
Family monthly income, RMB/yuan      
Low (<2000) 225 (15.1) −2.47 (−6.55, 1.612 0.235
Medium (2000–4000) 1100 (73.8) −1.9472 (−5.27, 1.38) 0.252
High (>4000) 166 (11.1) Ref.  
Health status      
Prepregnancy BMI      
Underweight (<18.5) 362 (24.3) −1.37 (−3.83, 1.09) 0.274
Normal (18.5–23.9) 1036 (69.5) Ref.  
Overweight or obesity (≥24.0) 93 (6.2) −1.79 (−6.16, 2.58) 0.421
Gestational weight gain      
Insufficient 352 (23.6) 2.80 (0.10, 5.50) 0.042
Normal 732 (49.1) Ref.  
Excessive 407 (27.3) −2.63 (−5.06, −0.19) 0.035
Parity      
Primipara 1292 (86.7) Ref.  
Multiparous 199 (13.3) −0.56 (−3.61, 2.48) 0.715
Complication of pregnancy a      
None 1265 (84.8) Ref.  
Yes 226 (15.2) −3.28 (−6.16, −0.40) 0.026
Prepregnancy lifestyle b      
Maternal alcohol consumptionc      
None 1266 (84.9) Ref.  
Any 225 (15.1) −1.09 (−3.98, 1.80) 0.461
Father smoking d      

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None 849 (56.9) Ref.  
One to five cigarettes daily 306 (20.5) 1.55 (−1.07, 4.17) 0.245
More than 6 cigarettes daily 336 (22.5) 1.08 (−1.47, 3.63) 0.408
Father alcohol consumption c      
None 292 (19.6) Ref.  
Any 1199 (80.4) 2.97 (0.37, 5.57) 0.025
Food frequency during pregnancy      
Egg intake      
≤3 times/wk 436 (29.2) Ref.  
>3 times/wk 1055 (70.8) 1.47 (−0.80, 3.75) 0.204
Milk intake      
≤3 times/wk 285 (19.1) Ref.  
>3 times/wk 1206 (80.9) 1.84 (−0.79, 4.47) 0.171
Birth outcomes      
Infant sex      
Male 791 (53.1) Ref.  
Female 700 (46.9) −2.22 (−4.29, −0.15) 0.035
Gestational age      
<37 wk 72 (4.8) −1.79 (−6.62, 3.03) 0.466
≥37 wk 1419 (95.2) Ref.  
Birth weight, kg      
<2500 g 43 (2.9) −2.97 (−9.15, 3.21) 0.346
≥2500 g 1448 (97.1) Ref.  
Season of birth      
Spring 597 (40.0) 10.22 (12.91, 7.53) <0.001
Summer 558 (37.4) −6.88 (−3.58, 30.17) <0.001
Autumn 234 (15.7) 40.94 (36.27, 45.62) <0.001
Winter 102 (6.8) Ref.  

a Complications of pregnancy included diabetes mellitus, hypertension, abnormal heart function, glandula thyreoidea disease,
intrahepatic cholestasis of pregnancy, and moderate and severe anemia.
b Prepregnancy lifestyle means lifestyle during up to 6 months before pregnancy. c Alcohol consumption was defined as any
alcohol consumption. d Father's smoking was defined as more than six cigarettes daily.

Mean cord blood concentrations of 25(OH)D were 3.9 nmol/L (95% CI, 1.2, 6.5) higher in neonates whose mother took vitamin D
supplementation >2 months compared with those whose mother did not take any supplementation (Figure 1A). This difference
remained significant when adjusted for season of birth (adjusted β = 3.8; 95% CI, 1.2, 6.4), when additionally adjusted for
prepregnancy BMI and GWG (adjusted β = 4.1; 95% CI, 1.5, 6.7), and when additionally adjusted for maternal sociodemographic
characteristics, prepregnancy lifestyle, health status, and birth outcomes (adjusted β = 3.5; 95%CI, 0.8, 6.2). Consistently,
compared with women without any vitamin D supplementation, the proportion of neonatal vitamin D deficiency was significantly
lower (79.9% vs 72.3%, P < 0.01) and the adjusted OR was 0.61 (95% CI, 0.43, 0.86) in women with vitamin D supplementation
for >2 months (Figure 1B). However, the mean cord blood levels of 25(OH)D in women with vitamin D supplementation for <2
months was not significantly different with that in women without any vitamin D supplementation.

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Figure 1.

Associations of maternal vitamin D supplementation with cord blood levels of 25(OH)D. (A) The difference of 25(OH)D levels in
cord blood and (B) the risk of neonatal vitamin D deficiency in group A (supplementation <2 months) and group B
(supplementation >2 months) compared to women without any vitamin D supplementation were assessed by using multiple linear
regression models and logistic regression models, respectively. Model 1 is unadjusted; model 2 is adjusted for season of birth;
models 3 and 4 are additionally adjusted for prepregnancy BMI and GWG and for maternal sociodemographic characteristics,
prepregnancy lifestyle, food intake during pregnancy, health status and birth outcomes, respectively.

Seasonal variation in vitamin D status is evident with seasonal variation being comparable in all three groups (Figure 2). With
stratification according to the seasons, the cord blood concentrations of 25(OH)D during winter (adjusted β = 3.4;95%CI 0.6, 6.3),
spring (adjusted β =3.8; 95% CI, 0.8, 6.9), summer (adjusted β = 6.6; 95% CI, 3.0, 10.3), and autumn (adjusted β = 6.0; 95% CI,
2.3, 9.6) in neonates whose mother took vitamin D supplementation for >2 months were both significantly higher than that in
neonates whose mother did not take any vitamin D supplementation. However, there were no differences between women with
vitamin D supplementation for <2 months and women without any vitamin D supplementation in the mean levels of cord blood
25(OH)D according to the seasons.

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Figure 2.

Seasonal patterns of 25(OH)D concentration among women without any vitamin D supplementation (nonsupplement group),
women with vitamin D supplementation for <2 months (supplement group A), and women with vitamin D supplementation for >2
months (supplement group B).

Figure 3 shows the ORs of SGA in association with maternal vitamin D supplementation status and increasing cord blood
concentrations of 25(OH)D. Cord blood concentrations of 25(OH)D significantly increased across the increasing duration of
maternal vitamin D supplementation. The medians and interquartile range of 25(OH)D levels among three groups were 34.3 (23.3
to 46.7) nmol/L, 35.2 (23.3 to 49.7) nmol/L and 37.9 (25.5 to 52.0) nmol/L, respectively. The adjusted risk of SGA in women with
vitamin D supplementation for >2 months were significantly decreased than for women without any vitamin D supplementation
(11.8% vs 6.9%; adjusted OR of 0.53; 95% CI, 0.32, 0.87). However, the risk of SGA in women with vitamin D supplementation for
<2 months was not significantly decreased in comparison with that in women without any vitamin D supplementation.

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Figure 3.

Risk of SGA in association with maternal vitamin D supplementation status and increasing cord blood concentrations of 25(OH)D.
Odd ratios are adjusted for maternal sociodemographic characteristics, prepregnancy lifestyle, food intake during pregnancy,
health status, and season of birth. Nonsupplement group means pregnant women without any vitamin D supplementation;
supplement group A means pregnant women with vitamin D supplementation for <2 months during pregnancy; supplement group
B means pregnant women with vitamin D supplementation for >2 months during pregnancy.

We further investigated the effect of birth seasons on fetal growth. There was no significant difference in the incidence of SGA
among the birth seasons across three groups. Despite that neonates in the nonsupplemented group who were born in the
summer/autumn had higher mean levels of 25(OH)D than neonates in the supplemented group B who were born in the
winter/spring (46.0 ±18.3 nmol/L vs 29.0 ± 14.0 nmol/L, P < 0.001), the incidence of SGA in the nonsupplemented group and
those born in the summer/autumn was still significantly increased compared with those in supplemented group B and those born
in the winter/spring (12.4% vs 7.6%, P = 0.020). Additionally, we investigated the association of 25(OH)D with calcium and
phosphorus in cord blood. The slight but significant linear relationships of 25(OH)D with calcium (r = 0.126, P < 0.001) and
phosphorus (r = 0.071, P = 0.006) were observed in all neonates (Supplemental Figure 1).

Discussion

To date, there was little evidence on the association of prenatal vitamin D supplementation with fetal growth from the developing
country. This study presents evidence about the effects of maternal vitamin D supplementation on cord blood concentrations of
25(OH)D and the risk of SGA in Chinese population. Although the effect is relatively modest, fetal growth restriction remains the
main contributor to mortality of infants and young children in developing countries,[32] which have higher infant mortality and half
of the global population. Consequently, the findings were associated with significant and clinical importance.

There is no consensus on the optimal dose of vitamin D supplementation during pregnancy, although a 2010 review of the vitamin
D requirements by the IOM resulted in a revised recommended daily allowance of 600 IU/d of vitamin D for women during
pregnancy.[24] The finding of this study suggested that neonates whose mother took 400 to 600 IU daily of vitamin D
supplementation for 2 months had a slight but significant increase (10.1% higher) in 25(OH)D levels at birth and the proportion of
vitamin D deficiency (< 50nmol/L) was reduced, compared with those whose mother did not take any vitamin D supplementation.

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However, > 70% of neonates whose mother took 400 to 600 IU daily of vitamin D supplementation were still vitamin D deficient at
birth. Given the association of sufficient neonatal vitamin D with a reduced risk of skeletal[23] and nonskeletal health disorders,[33]
the optimal level seems to be greater than the current dietary reference intake of 600 IU/d.

Several previous observational studies showed that maternal or fetal vitamin D levels in the upper range were linked to the
increased risk of fetal growth restriction,[12] smaller head circumference,[34] and schizophrenia[35] in human offspring. These
observational findings suggested that caution is necessary with regard to higher levels of prenatal vitamin D supplementation.
However, new evidence from well-designed randomized controlled trial (RCT) studies indicated that maternal vitamin D
supplementation with ≥4000 IU of vitamin D has great benefit and is safe.[36] Vitamin D supplementation of 4000 IU/d for pregnant
women is most effective in achieving sufficiency in all women and their neonates.[22,37] The great benefits on reducing risk of
maternal comorbidities and improving neonatal outcomes have been reported in several RCT studies,[21,38–41] and the long-term
effect of prenatal vitamin D supplementation on asthma or recurrent wheezing in offspring by age 3 years also has been
observed.[42,43] Inconsistently, a few RCT studies with prenatal ≥4000 IU/d vitamin D supplementation have not found significant
effects on anthropometric measurements of infants at birth and at 12 months of age.[7,22,23] Therefore, larger and longer follow-up
RCT studies including more diverse race/ethnic participants are needed to determine the optimal dose of prenatal vitamin D
supplementation.

Our study suggested that the slight but significantly increased fetal levels of 25(OH)D owing to the 400 to 600 IU/d vitamin D
supplementation during pregnancy may essentially contribute to the improvement of fetal growth. However, many of today's
practicing obstetricians in China are not aware of the vitamin D content in prenatal vitamins. Most pregnant women did not receive
the recommendation about supplementation for vitamin D during pregnancy. Alternativley, in China, pregnant women pay for
vitamin D supplements directly out of pocket. Additional vitamin D supplementation during the whole pregnancy increases the
family financial burden, which will affect the ability of pregnant women to receive vitamin D supplementation. In our findings, more
than half of the participants could not adhere to supplementation for 2 months during pregnancy. Therefore, it is a reasonable and
cautious strategy in the current developing countries to stepwise increase routine vitamin D supplementation levels from 600 IU/d
according the current recommendation by IOM to 4000 IU/d based on the evidence of new RCT studies. Additionally, integrated
intervention including enhancing the awareness of vitamin D in health workers, adding vitamin D into the national reimbursement
drug inventory, and fortification of food with vitamin D could further improve the intake of vitamin D in the developing countries.

Although we observed a significant linear relationships of 25(OH)D with calcium and phosphorus in cord blood, the mean levels of
calcium and phosphorus between the non supplemented group and the supplemented group had no difference. Thus, the
regulation of 25(OH)D on fetal skeletal metabolism of calcium and phosphorus was unlikely associated with the improvement of
fetal growth observed in this study. The roles of a low dose of vitamin D supplementation on placental function, metabolism of
glucose and lipids, and inflammation and genomic alterations should get more attention.[15,44,45]

Unexpectedly, our study showed that the incidence of SGA of neonates in the non supplemented group and born in the
summer/autumn, whose 25(OH)D was in the highest levels across seasons, was still significantly increased compared with those
in the supplemented group B and born in the winter/spring. The finding suggested that birth season is a critical predictor for fetal
25(OH)D at birth, but not for fetal growth. The neonates in the non supplemented group had the lowest levels of 25(OH)D in any
season (even in the summer) compared with the other two groups in the same season. These results indicate that the fetuses in
the non supplemented group might always have lower 25(OH)D levels during the whole pregnancy than do fetuses in the
supplemented group. Thus, we thought that the improvement in fetal growth observed in this study should be largely attributed to
the maternal vitamin D supplementation during the pregnancy instead of the seasonal 25(OH)D levels at birth.

The prospective study design, relatively large sample size, strict selection criteria for the participants, statistical adjustments for
several potential confounding factors such as food intake during pregnancy, GWG, and season of birth add credence to our data.
Unlike rigorous clinical supplement trials, this study was designed to focus on the natural behavior of vitamin D supplementation
during pregnancy. We are limited in our ability to strongly control the compliance of vitamin D supplementation. Therefore, the
duration of supplementation in this study was used to reflect the compliance of vitamin D supplementation. Individual variations of
duration and dose among pregnant women with vitamin D supplementation for >2 months may slightly fluctuate the association
descripted in this study. Additionally, we also could not exclude the effect of other supplementations such as calcium.

The findings in this study suggest that maternal vitamin D supplementation during pregnancy as recommended by the IOM
resulted in slight but significantly higher fetal levels of 25(OH)D and essentially improved fetal growth. Further studies need to
identify the effects that higher intakes of vitamin D supplementation would have and consequently to construct the appropriate
strategies for maternal vitamin D supplementation in developing countries.

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Financial Support
This study was supported by National Natural Science Foundation of China Grants 81472991, 81330068, 81373012, and
81573164 and Key Project Foundation for the Talents by Anhui Educational Commission Grant 2013SQRL020ZD.

J Clin Endocrinol Metab. 2018;103(1):244-252. © 2018 Endocrine Society

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