European Journal of Clinical Nutrition (2014), 1–6 © 2014 Macmillan Publishers Limited All rights reserved 0954-3007/14 www.nature.com/ejcn
ORIGINAL ARTICLE
Associations between 25-hydroxyvitamin D levels and pregnancy outcomes: a prospective observational study in southern China J Zhou1,2,6, L Su3,6, M Liu4, Y Liu1, X Cao1, Z Wang5 and H Xiao1 BACKGROUND/OBJECTIVES: Observational studies relating 25-hydroxyvitamin D (25(OH)D) and pregnancy outcomes have reported conflicting results. The aim was to assess maternal 25(OH)D status and its association with pregnancy outcomes. A prospective observational study was carried out in Guangzhou city (23 ºN), China. SUBJECTS/METHODS: Pregnant women (n = 2960) and healthy controls (n = 100) were recruited at a teaching hospital. Maternal 25(OH)D levels were measured at 16–20-week gestation. The pregnant women, if met inclusion and exclusion criteria, were enrolled in further analysis for pregnancy outcomes (n = 1953). RESULTS: Mean serum 25(OH)D in pregnant women was 27.03 ± 7.92 ng/ml. In total, 18.9 and 48.6% of pregnant women had low (25(OH)D less than or equal to 20 ng/ml) and medium level (25(OH)D 21–29 ng/ml) of vitamin D, respectively. 25(OH)D was highest in summer and lowest in winter, which showed a positive correlation with temperature (R = 0.942) and calcium (R = 0.074). Most maternal outcomes (premature rupture of membranes break, polyhydramnios, oligohydramnios, pre-eclampsia, cesarean section), fetal outcomes (spontaneous abortions, medically induced labor, fetal death, fetal distress, fetal growth restriction) and neonatal outcomes (malformations, birth weight and height, low birth weight, macrosomia, small-for-gestational age, score of Apgar 1′,5′, asphyxia of newborn) were not significantly different between groups, but prevalence of gestational diabetes (adjusted odds ratio (OR) 1.017; 95% confidence interval (CI) 1.002–1.033) and preterm delivery (adjusted OR 1.038; 95% CI 1.018–1.059) in high level group (25(OH)D ⩾ 30 ng/ml) was higher than that in low and medium level groups. CONCLUSIONS: The prevalence of low level of vitamin D (serum 25OHD ⩽ 20 ng/ml) was 18.9% among pregnant women in southern China. There were no significant differences in most adverse pregnancy outcomes among pregnant women with different levels of vitamin D at 16–20-week gestation except for higher prevalence of gestational diabetes and preterm delivery in women with high level of vitamin D, possibly related to the older age and higher body mass index of this group. European Journal of Clinical Nutrition advance online publication, 28 May 2014; doi:10.1038/ejcn.2014.99
INTRODUCTION The consequences of maternal, fetal and neonatal complications, including death and disabilities, make up the largest burden of diseases affecting women in developing countries. An estimated 9–10% of pregnant women (about 14 million) per year suffer from acute maternal complications worldwide.1,2 Vitamin D deficiency in pregnant women3–5 is a great concern for pregnancy outcomes. Numerous potential associations have been reported between various pregnancy outcomes and single measurement of serum 25-hydroxyvitamin D (25(OH)D). 25(OH)D is the major storage form of vitamin D in the human, so it can be measured in blood to determine the overall vitamin D status.6,7 Some studies suggest that low 25(OH)D predicts increased risk of gestational diabetes,8 pre-eclampsia,9 threatened preterm birth,10 cesarean section11 and low birth weight,12 although other studies found no significant associations with these outcomes.13–17 As a recent review of vitamin D and pregnancy outcomes concluded, the
quality of evidence was low.18 To date, no consensus exists regarding optimal vitamin D level in pregnancy. The objective of this present large prospective observational study was to assess maternal vitamin D status in Chinese pregnant women and its association with pregnancy outcomes, and thus provide evidence for clinical recommendations regarding vitamin D supplementation and potential screening in the care of pregnancy. MATERIALS AND METHODS Study population In the present study, participants were recruited in Guangzhou city (located 23.1ºN) between September 2010 and August 2011, which followed up to 2012. All pregnant women during this period visiting our hospital were invited to take part. The response rate was 96.1% (n = 2960). One hundred non-pregnant healthy women matched by age were randomly selected from February to March 2012 to establish a reference range of vitamin D status for healthy women living in the area, as there is
1 Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, People’s Republic of China; 2Department of Endocrinology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 108 Yanjiangxi Road, Guangzhou, People’s Republic of China; 3Department of Geriatrics, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, People’s Republic of China; 4Department of Laboratory, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, People’s Republic of China and 5Department of Obstetrics, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, People’s Republic of China. Correspondence: Dr H Xiao or Dr Z Wang, Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou 510080, People’s Republic of China. E-mail: [email protected] or [email protected] 6 These authors contributed equally to this work. Received 19 July 2013; revised 10 April 2014; accepted 13 April 2014
Vitamin D status and pregnancy outcomes J Zhou et al
2 no general consensus on the optimal 25OHD level for pregnant women. The use of vitamin D and calcium supplements were recorded. The pregnant women, if met inclusion and exclusion criteria, were enrolled in further analysis for pregnancy outcomes (n = 1953). They were evaluated and data were recorded at antenatal cares (clinical characteristics were recorded at first antenatal care) and after delivery. Written informed
Figure 1.
consent and approval were obtained from all subjects and the institutional ethical committee (Figure 1).
Criteria for patient eligibility Inclusion criteria: a, age ⩾ 18 years; b, delivery (including the normal delivery, abortion, induced labor) in our hospital.
Study profile.
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Vitamin D status and pregnancy outcomes J Zhou et al
3 Exclusion criteria: a Lack of informed consent; b Increased liver enzymes by a factor of two or more above upper normal limits; c Chronic disease and tumor; d Before 13 weeks of gestation, including 13 weeks, pregnant women are accompanied by severe infections, trauma or in perioperative; e Before 13 weeks of gestation, including 13 weeks, pregnant women take corticosteroids, drug abuse (including alcohol).
Categorization Based on the 25OHD level, we categorize the pregnant women into three groups: (1) group A (low level) (⩽20 ng/ml), (2) group B (medium level) (21–29 ng/ml) and (3) group C (high level) (⩾30 ng/ml), according to reference values for an adult population.19,20
Definition of seasons and temperature Seasons of sample collection were defined as winter (December, January, February), spring (March, April, May), summer (June, July, August) and fall (September, October, November). Data of temperature were obtained from the Meteorological Bureau of Guangdong province.
Measurement Maternal blood was collected in the non-fasting condition at 16–20-week gestation. Serum were stored at − 70°C until they were analyzed for 25(OH)D. Serum 25(OH)D was assayed by using electrochemiluminescence immunoassay (Roche Diagnostics, Mannheim, Germany). The assay correlated well with liquid chromatography–tandem mass spectrometry and high-performance liquid chromatography.21 The elecsys assay recognized only 25(OH) D. The assay has a sensitivity of 4 ng/ml, an intraand inter-assay coefficient of variation of 6.6% and 5.4%, respectively. None of the values were below the lower limit of detection. Serum total calcium, albumin and inorganic phosphorus were analyzed spectrophotometrically (Sigma Diagnostics, St Louis, MO, USA).
Pregnancy outcomes The following pregnancy outcomes were recorded. (1) Maternal outcomes: premature rupture of membranes break (when the membranes that hold the amniotic fluid break too early), gestational diabetes (all women undergo a 75-g oral glucose tolerance test at 24–28 weeks of gestation, the diagnosis of gestational diabetes is made when any of the following plasma glucose values are exceeded: fasting: ⩾ 92 mg/dl,1 h: ⩾ 180 mg/dl, 2 h: ⩾ 153 mg/dl), polyhydramnios (a state where liquor amnii exceeds 2000 ml), oligohydramnios (a state where liquor amnii less than 300 ml in the third trimester of pregnancy), pre-eclampsia (pre-eclampsia is defined as high blood pressure and excess protein in the urine after 20 weeks of pregnancy in a woman who previously had normal blood pressure), cesarean section, preterm delivery (a live birth before 37 completed weeks of gestation). (2) Fetal outcomes: spontaneous abortion (fetal loss after enrollment but before 20 completed weeks of gestation), medically induced labor (termination of pregnancy because of serious maternal or fetal risks), fetal death (intrauterine fetal demise after 20 completed weeks of
Table 1.
gestation), fetal distress (defined as depletion of oxygen and accumulation of carbon dioxide, leading to a state of ‘hypoxia and acidosis’ during intra-uterine life. Baseline fetal heart rate o 110 bpm, sustained >5 min; late deceleration without variability; fetal heart rate 110–160 bpm without variability and accelerations), fetal growth restriction (deviation in expected fetal growth pattern (10th percentile), measuring height of the upper portion of the uterus and evaluate the growth of the baby by ultrasound). (3) Neonatal outcomes: malformations (including nervous system, circulatory system, digestive system, reproductive system, urinary system, musculoskeletal, chromosome disorder and others), birth weight and height, low birth weight (o2500 g), macrosomia (>4000 g), small-forgestational-age (weight o10th percentile or 2SD at birth), score of Apgar 1′,5′, asphyxia of newborn (a failure to start regular respiration within a minute of birth).
Statistical analysis SPSS software (version 17.0; SPSS, Chicago, IL, USA) was used for all statistical calculations. Values are presented as means ± s.d. or mean (95% confidence interval (CI)) for variables with normal distribution. Comparisons of normally distributed value among more than two groups were performed with analysis of variance (one-way analysis of variance test). Proportion was compared by using the χ2 test. Correlations were studied by using Pearson’s correlation coefficient. Logistic regression analysis was used to assess the associations between different levels of vitamin D and pregnancy outcomes after adjusting for relevant confounding factors (maternal age, systolic/diastolic pressure, prepregnancy body mass index (BMI) and serum calcium). A P-value of 0.05 defined statistical significance.
RESULTS Of 3080 pregnant womsen visited the hospital, 96.1% (n = 2960) took part in; furthermore, 63.4% (n = 1953) met inclusion criteria and were enrolled in further analysis for pregnancy outcomes. Characteristics of pregnant women At baseline, pregnant women in high level group were significantly older than the women in low and medium level groups (mean age, 30.3 ± 3.9 years vs 29.2 ± 3.5 years and 29.5 ± 3.6 years; P o0.01) and had a marginally higher prepregnancy BMI (mean, 20.67 ± 2.64 vs 20.28 ± 2.52 and 20.24 ± 2.51 kg/m2, respectively; P = 0.05). Systolic and diastolic pressure and percentage of regular vitamin D supplementation were not significantly different among the three groups (Table 1). Vitamin D status in pregnant women Mean serum 25(OH)D in all pregnant women was 27.03 ± 7.92 ng/ml (n = 2960). 25(OH)D in low, medium and high level groups were 16.59 ± 2.6, 24.87 ± 2.79 and 35.88 ± 5.2 ng/ml, respectively (Table 1). In total, 18.9% (n = 559) and 48.6% (n = 1438) of pregnant women had low level and medium level of vitamin D, respectively. There were only 16 (0.54%) pregnant women who had a 25(OH)D over 50 ng/ml. Non-pregnant healthy women (n = 100) matched by age (29.50 ± 3.94 vs 29.43 ± 2.92, P = 0.895) had a lower level of 25(OH)D (18.22 vs 27.03 ng/ml,
Clinical characteristics of pregnant women at 16–20-week gestation (n = 1953)
25-hydroxyvitamin D (ng/ml) Age (year) Systolic pressure (mmHg) Diastolic pressure (mmHg) Prepregnancy body mass index (kg/m2) Regular vitamin D supplementa (%)
Group A
Group B
Group C
P-value
16.59 ± 2.60 29.2 ± 3.5 119.2 ± 10.8 72.1 ± 9.4 20.28 ± 2.52 72.5
24.87 ± 2.79 29.5 ± 3.6 119.3 ± 11.1 73.7 ± 24.5 20.44 ± 2.51 73.4
35.88 ± 5.20 30.3 ± 3.9 119.4 ± 11.2 72.5 ± 8.5 20.67 ± 2.64 73.5
o0.01 o0.01 0.924 0.277 0.050 0.356
Defined as Vitamin D3 ⩾ 500 IU per day more than 3 days per week.
a
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Vitamin D status and pregnancy outcomes J Zhou et al
4 Po 0.001) and higher prevalence of low level of vitamin D than pregnant women (71.0% vs 18.9%, P o 0.001). There was seasonal variation in serum 25(OH)D concentration. Maternal 25(OH)D was highest in summer (28.52 ± 7.93 ng/ml, n = 745) and lowest in winter (24.99 ± 7.50 ng/ml, n = 664) (P o 0.001). The prevalence of low level of vitamin D was 14.2% in summer and 26.2% in winter (Table 2). 25(OH)D level in pregnant women was positively correlated with temperature (R = 0.942, R2 = 0.877, P o0.001) as shown by linear regression analysis. The regression equation was: 25(OH) D = (0.214 × T)+22.386. Serum 25(OH)D levels in pregnant women were positively correlated with serum calcium as well (R = 0.074, R2 = 0.005, P = 0.001). Serum calcium concentration in high level group was 2.23 ± 0.14 mmol/l, which was higher than that in low level (2.20 ± 0.12 mmol/l) and medium level group (2.21 ± 0.13 mmol/l) (P = 0.005). The regression equation was: Ca = 2.178 × 25(OH)D) +22.386 Association of vitamin D status and pregnancy outcomes Most maternal outcomes (premature rupture of membranes break, polyhydramnios, oligohydramnios, pre-eclampsia, cesarean
Table 2.
DISCUSSION In this large single center prospective observational study, unexpected high prevalence of low level of vitamin D was demonstrated in pregnant women at 16–20-week gestation who are living in a tropical region with abundant sunshine and regular
Percentage of vitamin D status in pregnant women at 16–20-week gestation in different seasons Winter
Low level Medium level High level
Table 3.
section) were not significantly different between the three groups. There were also no significant differences in fetal (spontaneous abortions, medically induced labor, fetal death, fetal distress, fetal growth restriction) and neonatal outcomes (malformations, birth weight and height, low birth weight, macrosomia, small-forgestational age, score of Apgar 1′,5′, asphyxia of newborn) between groups. Prevalence of gestational diabetes and preterm delivery in high level group (20.25% and 10.53%) was higher than that in low (12.97% and 6.04%) and medium level group (16.28% and 7.62%) (Table 3). Significant associations were also found between vitamin D status and gestational diabetes and preterm delivery (adjusted odds ratio (OR) 1.017, 1.039, respectively) (Table 4). However, there was no significant association between other pregnancy outcomes with different levels of vitamin D at 16–20-week gestation (Table 4).
Spring
Summer
Fall
n
%
n
%
n
%
n
%
174 336 154
26.2 50.6 23.2
161 400 254
19.8 49.1 31.2
106 335 304
14.2 45.0 40.8
118 367 260
15.8 49.3 34.9
Outcomes of pregnant women, fetuses and live births grouped according to vitamin D status
Pregnancy outcomes
Group A
Group B
P-value
Group C
n
%
n
%
n
%
Maternal outcomes Premature rupture of membranes break Gestational diabetes Polyhydramnios Oligohydramnios Pre-eclampsia Cesarean section Preterm delivery
370 77 48 13 8 13 200 22
20.81 12.97 3.51 2.16 3.51 55.10 6.04
946 215 154 37 15 36 547 71
22.73 16.28 3.91 1.59 3.81 58.57 7.62
637 134 129 31 14 25 380 66
21.04 20.25 4.87 2.20 3.92 60.51 10.53
0.425 0.099 0.173 0.421 0.900 0.220 0.052
Fetal outcomes Spontaneous abortion Medically induced labor Fetal death Fetal growth restriction
364 1 5 3 3
0.27 1.37 0.82 0.82
932 6 8 4 5
0.64 0.86 0.43 0.54
627 2 8 7 10
0.32 1.28 1.12 1.59
0.813 0.207 0.058 0.337
Neonatal outcomes Malformations Birth height (cm) Birth weight (kg) Low birth weight Macrosomia Small-for-gestational-age infants Apgar 1′ Apgar 5′ Asphyxia of newborn
364 13
3.57
932 37
3.97
627 22
3.51 49.2 ± 2.9 3.141 ± 0.484 12 1.91 17 2.71 4 0.64 9.83 ± 0.75 9.96 ± 0.43 14 2.23
0.779 0.053 0.461 0.647 0.458 0.793 0.673 0.497 0.421
49.5 ± 1.9 3.138 ± 0.434 11 3.02 6 1.65 4 1.10 9.81 ± 0.73 9.98 ± 0.22 4 1.10
49.4 ± 2.1 3.166 ± 0.471 10 1.07 22 2.36 3 0.32 9.82 ± 0.66 9.97 ± 0.30 18 1.93
Data expressed as mean ± s.d., number (sum of subgroup) or %. P-values when comparing low level Group A and medium level Group B with high level Group C (used logistic regression analysis).
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Vitamin D status and pregnancy outcomes J Zhou et al
5 Table 4.
Associations between pregnancy outcomes and vitamin D status by multiple regression analysis (n = 1953) Odds ratio
Lower of 95% confidence interval for odds ratio
Upper of 95% confidence interval for odds ratio
P-value
Maternal outcomes Premature rupture of membranes break Gestational diabetes Polyhydramnios Oligohydramnios Pre-eclampsia Cesarean section Preterm delivery
0.997 1.017 1.027 1.011 1.003 1.003 1.039
0.983 1.001 0.999 0.970 0.965 0.990 1.018
1.011 1.033 1.056 1.054 1.043 1.015 1.060
0.642 0.034 0.059 0.609 0.872 0.671 0.000
Fetal outcomes Spontaneous abortion Medically induced labor Fetal death Fetal distress Fetal growth restriction
1.036 1.016 1.023 0.995 1.036
0.949 0.959 0.958 0.978 0.983
1.132 1.076 1.094 1.013 1.092
0.429 0.598 0.497 0.601 0.190
Neonatal outcomes Malformations Low birth weight Macrosomia Small-for-gestational-age infants Asphyxia of newborn
1.016 1.016 1.010 0.988 1.032
0.984 0.972 0.972 0.916 0.991
1.049 1.061 1.051 1.067 1.074
0.338 0.486 0.603 0.762 0.128
Pregnancy outcomes
Logistic regression analysis. Odds ratio for associations between pregnancy outcomes and vitamin D status. Odds ratio adjusted for maternal age, systolic/ diastolic pressure, prepregnancy body mass index and serum calcium.
use of prenatal vitamin D. 25(OH)D was highest in summer and lowest in winter, and was positively correlated with the average temperature of the month. No associations were observed between maternal 25(OH)D status and majority of adverse pregnancy outcomes except for higher prevalence of gestational diabetes and preterm delivery in women with high level vitamin D. Hypovitaminosis D is a significant problem in China and across the globe. Two cross-sectional studies with small sample sizes conducted in Shanghai22 (located 31.1ºN) and Chengdu23 (located 30.7ºN) found that 69% and 57.1% of pregnant women had vitamin D deficiency with mean levels of 17.57 ± 11.44 ng/ml and 14.38 ± 7.88 ng/ml, respectively. Our present study demonstrated high prevalence of low (18.9%) level of vitamin D in Chinese pregnant women living in Guangzhou, although it is lower than that in Shanghai and Chengdu. Our data showed that pregnant women living in Guangzhou (located 23.1ºN) had higher mean serum 25(OH)D level (27.03 ± 7.92 ng/ml) than those living in Shanghai and Chengdu, two cities locating at higher latitude. Higher latitude might relate to less vitamin D production in the skin. Regular use of prenatal vitamin D (over 70%) in our study population might be another contributor to higher vitamin D level in pregnant women living in Guangzhou. Seasonal variation in 25(OH)D status was observed in American,4 Australian (22)24 and Indian25 pregnant women. Similar observation was found in our study which showed a strong positive correlation between serum 25(OH)D level and the average temperature of the month. Highest maternal serum 25(OH)D level in summer and lowest in winter was evidenced in this study. Despite growing interest in the relationships between vitamin D status during pregnancy and maternal and neonatal outcomes, the results of previous reports are inconsistent. Most recently, a systematic review suggested protective effects of vitamin D supplementation on low birth weight (risk ratio = 0.40 (95% CI 0.23, 0.71)) and non-significant but suggestive effects of daily supplementation on small-for-gestational age (risk ratio = 0.67 (0.40, 1.11)),18 while another meta-analysis performed by Rabi DM26 found insufficient serum levels of 25-OHD were associated © 2014 Macmillan Publishers Limited
with gestational diabetes (pooled OR 1.49, 95% CI 1.18–1.89), preeclampsia (1.79, 1.25–2.58) and small-for-gestational age infants. In our present study, there were no significant differences in most adverse pregnancy outcomes among pregnant women with different levels of vitamin D at 16–20-week gestation. To our surprise, our study showed that prevalence of gestational diabetes (adjusted OR 1.017; 95% CI 1.001–1.033) and preterm delivery (adjusted OR 1.039; 95% CI 1.018–1.060) in high level group was higher than that in low and medium level groups. In experimental studies, vitamin D is thought to have both direct (through activation of vitamin D receptor ) and indirect (via regulation of calcium homeostasis) effects on various mechanisms related to the pathophysiology of diabetes including pancreatic β-cell dysfunction, impaired insulin action and systemic inflammation.27 In our study, pregnant women in high level group were older and had slightly higher prepregnant BMI than those in low and medium level groups. Older age and higher BMI are traditional risk factors for gestational diabetes and might contribute to higher prevalence of gestational diabetes in pregnant women with high level of vitamin D in our findings. Other risk factors such as smoking, alcohol, gestational weight gain, socio-economic status may also contribute. Future well-designed randomized clinical trials are required to elucidate whether vitamin D supplementation might interfere with glucose metabolism in pregnancy. Until now, there are limited observational data available on the relationship of vitamin D and preterm delivery. In an observational study, gestation length was 0.7 week shorter in infants of 27 mothers with low 25(OH)D (o 28 nmol/l) at 28–32 week vs babies whose mothers had higher concentrations.28 In another nested case-control study with women with prior spontaneous preterm birth, serum 25(OH)D concentration was not associated with preterm birth.13 More intervention and observational studies are needed to assess the potential for vitamin D to influence the risk of preterm delivery. Our study was limited by lack of data on sunlight exposure, dietary vitamin D intake, measurement of 25(OH)D from cord blood and infants in late pregnancy and those who were not delivered in our hospital. Low prevalence of some pregnancy European Journal of Clinical Nutrition (2014) 1 – 6
Vitamin D status and pregnancy outcomes J Zhou et al
6 outcomes may cause false negative results. The relationships between vitamin D status in pregnant women and neonatal/ infants’ growth and health outcomes have not been observed as well in this study. There are reports that low vitamin D status of pregnant mothers could be related to adverse health outcomes in the offspring.29,30 A long follow-up study is imperative to confirm this observation, and observe long-term effects of vitamin D on women and infants. Our study is a large prospective observational study evaluating vitamin D level and its association with pregnancy outcomes, with a sample size of 1953 pregnant participants. Many pregnancy outcomes were evaluated in our study, such as premature rupture of membranes break, fetal growth restriction, malformations, macrosomia and asphyxia of newborn, have not been reported previously. New evidence concerning the association between vitamin D level and pregnancy outcomes was demonstrated in our study. This large prospective observational study showed a high prevalence of low level of vitamin D among pregnant women in southern China who are thought to have sufficient exposure to ultraviolet B radiation and who are on regular use of prenatal vitamin D supplement. There were no significant differences in most adverse pregnancy outcomes among pregnant women with different levels of vitamin D at 16–20-week gestation except for higher prevalence of gestational diabetes and preterm delivery in women with high level of vitamin D, possibly related to the older age and higher BMI of this group. More well-designed randomized prospective clinical trials of vitamin D supplement during pregnancy are needed to evaluate the potential role of vitamin D to prevent adverse outcomes. CONFLICT OF INTEREST The authors declare no conflict of interest.
AUTHOR CONTRIBUTIONS JZ performed experiments, analysed data and wrote the paper. LS searched literature, analysed data and wrote the paper. JZ and LS contributed equally to this work. ML was involved in performing the 25(OH)D measurements. YL and XC interpretated data. ZW was involved in patient care and data collection. HX designed the study and wrote the paper.
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8 Parlea L, Bromberg IL, Feig DS, Vieth R, Merman E, Lipscombe LL. Association between serum 25-hydroxyvitamin D in early pregnancy and risk of gestational diabetes mellitus. Diabet Med 2012; 29: e25–e32. 9 Baker AM, Haeri S, Camargo Jr CA, Stuebe AM. A nested case-control study of midgestation vitamin D deficiency and risk of severe preeclampsia. J Clin Endocrinol Metab 2010; 95: 5105–5109. 10 Shibata M, Suzuki A, Sekiya T, Sekiguchi S, Asano S, Udagawa Y et al. High prevalence of hypovitaminosis D in pregnant Japanese women with threatened premature delivery. J Bone Miner Metab 2011; 29: 615–620. 11 Merewood A, Mehta SD, Chen TC, Bauchner H, Holick MF. Association between vitamin D deficiency and primary cesarean section. J Clin Endocrinol Metab 2009; 94: 940–945. 12 Gernand AD, Simhan HN, Klebanoff MA, Bodnar LM. Maternal serum 25-hydroxyvitamin D and measures of newborn and placental weight in a U.S. Multicenter Cohort Study. J Clin Endocrinol Metab 2013; 98: 398–404. 13 Thorp J, Camargo C, McGee P, Harper M, Klebanoff M, Sorokin Y et al. Vitamin D status and recurrent preterm birth: a nested case-control study in high-risk women. BJOG 2012; 119: 1617–1623. 14 Charatcharoenwitthaya N, Nanthakomon T, Somprasit C, Chanthasenanont A, Chailurkit LO, Pattaraarchachai J et al. Maternal vitamin D status, its associated factors and the course of pregnancy in Thai women. Clin Endocrinol (Oxf) 2013; 78: 126–133. 15 Brunvand L, Shah SS, Bergstrom S, Haug E. Vitamin D deficiency in pregnancy is not associated with obstructed labor. A study among Pakistani women in Karachi. Acta Obstet Gynecol Scand 1998; 77: 303–306. 16 Yu CK, Ertl R, Skyfta E, Akolekar R, Nicolaides KH. Maternal serum vitamin D levels at 11-13 weeks of gestation in preeclampsia. J Hum Hypertens 2012; 27: 115–118. 17 Farrant HJ, Krishnaveni GV, Hill JC, Boucher BJ, Fisher DJ, Noonan K et al. Vitamin D insufficiency is common in Indian mothers but is not associated with gestational diabetes or variation in newborn size. Eur J Clin Nutr 2009; 63: 646–652. 18 Thorne-Lyman A, Fawzi WW. Vitamin D during pregnancy and maternal, neonatal and infant health outcomes: a systematic review and meta-analysis. Paediatr Perinat Epidemiol 2012; 26(Suppl 1): 75–90. 19 Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357: 266–281. 20 Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R. Estimates of optimal vitamin D status. Osteoporos Int 2005; 16: 713–716. 21 Emmen JM, Wielders JP, Boer AK, van den Ouweland JM, Vader HL. The new Roche Vitamin D total assay: fit for its purpose? Clin Chem Lab Med 2012; 1–4. 22 Tao M, Shao H, Gu J, Zhen Z. Vitamin D status of pregnant women in Shanghai, China. J Matern Fetal Neonatal Med 2012; 25: 237–239. 23 Wang J, Yang F, Mao M, Liu DH, Yang HM, Yang SF. High prevalence of vitamin D and calcium deficiency among pregnant women and their newborns in Chengdu, China. World J Pediatr 2010; 6: 265–267. 24 Bowyer L, Catling-Paull C, Diamond T, Homer C, Davis G, Craig ME. Vitamin D, PTH and calcium levels in pregnant women and their neonates. Clin Endocrinol (Oxf) 2009; 70: 372–377. 25 Marwaha RK, Tandon N, Chopra S, Agarwal N, Garg MK, Sharma B et al. Vitamin D status in pregnant Indian women across trimesters and different seasons and its correlation with neonatal serum 25-hydroxyvitamin D levels. Br J Nutr 2011; 106: 1383–1389. 26 Aghajafari F, Nagulesapillai T, Ronksley PE, Tough SC, O'Beirne M, Rabi DM. Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies. BMJ 2013; 346: f1169. 27 Draznin B, Sussman KE, Eckel RH, Kao M, Yost T, Sherman NA. Possible role of cytosolic free calcium concentrations in mediating insulin resistance of obesity and hyperinsulinemia. J Clin Invest 1988; 82: 1848–1852. 28 Morley R, Carlin JB, Pasco JA, Wark JD. Maternal 25-hydroxyvitamin D and parathyroid hormone concentrations and offspring birth size. J Clin Endocrinol Metab 2006; 91: 906–912. 29 Zhu K, Whitehouse AJ, Hart P, Kusel M, Mountain J, Lye S et al. Maternal vitamin D status during pregnancy and bone mass in offspring at 20 years of age: a prospective cohort study. J Bone Miner Res 2013; 29: 1088–1095. 30 Whitehouse AJ, Holt BJ, Serralha M, Holt PG, Kusel MM, Hart PH. Maternal serum vitamin D levels during pregnancy and offspring neurocognitive development. Pediatrics 2012; 129: 485–493.
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ORIGINAL ARTICLE
Associations between 25-hydroxyvitamin D levels and pregnancy outcomes: a prospective observational study in southern China J Zhou1,2,6, L Su3,6, M Liu4, Y Liu1, X Cao1, Z Wang5 and H Xiao1 BACKGROUND/OBJECTIVES: Observational studies relating 25-hydroxyvitamin D (25(OH)D) and pregnancy outcomes have reported conflicting results. The aim was to assess maternal 25(OH)D status and its association with pregnancy outcomes. A prospective observational study was carried out in Guangzhou city (23 ºN), China. SUBJECTS/METHODS: Pregnant women (n = 2960) and healthy controls (n = 100) were recruited at a teaching hospital. Maternal 25(OH)D levels were measured at 16–20-week gestation. The pregnant women, if met inclusion and exclusion criteria, were enrolled in further analysis for pregnancy outcomes (n = 1953). RESULTS: Mean serum 25(OH)D in pregnant women was 27.03 ± 7.92 ng/ml. In total, 18.9 and 48.6% of pregnant women had low (25(OH)D less than or equal to 20 ng/ml) and medium level (25(OH)D 21–29 ng/ml) of vitamin D, respectively. 25(OH)D was highest in summer and lowest in winter, which showed a positive correlation with temperature (R = 0.942) and calcium (R = 0.074). Most maternal outcomes (premature rupture of membranes break, polyhydramnios, oligohydramnios, pre-eclampsia, cesarean section), fetal outcomes (spontaneous abortions, medically induced labor, fetal death, fetal distress, fetal growth restriction) and neonatal outcomes (malformations, birth weight and height, low birth weight, macrosomia, small-for-gestational age, score of Apgar 1′,5′, asphyxia of newborn) were not significantly different between groups, but prevalence of gestational diabetes (adjusted odds ratio (OR) 1.017; 95% confidence interval (CI) 1.002–1.033) and preterm delivery (adjusted OR 1.038; 95% CI 1.018–1.059) in high level group (25(OH)D ⩾ 30 ng/ml) was higher than that in low and medium level groups. CONCLUSIONS: The prevalence of low level of vitamin D (serum 25OHD ⩽ 20 ng/ml) was 18.9% among pregnant women in southern China. There were no significant differences in most adverse pregnancy outcomes among pregnant women with different levels of vitamin D at 16–20-week gestation except for higher prevalence of gestational diabetes and preterm delivery in women with high level of vitamin D, possibly related to the older age and higher body mass index of this group. European Journal of Clinical Nutrition advance online publication, 28 May 2014; doi:10.1038/ejcn.2014.99
INTRODUCTION The consequences of maternal, fetal and neonatal complications, including death and disabilities, make up the largest burden of diseases affecting women in developing countries. An estimated 9–10% of pregnant women (about 14 million) per year suffer from acute maternal complications worldwide.1,2 Vitamin D deficiency in pregnant women3–5 is a great concern for pregnancy outcomes. Numerous potential associations have been reported between various pregnancy outcomes and single measurement of serum 25-hydroxyvitamin D (25(OH)D). 25(OH)D is the major storage form of vitamin D in the human, so it can be measured in blood to determine the overall vitamin D status.6,7 Some studies suggest that low 25(OH)D predicts increased risk of gestational diabetes,8 pre-eclampsia,9 threatened preterm birth,10 cesarean section11 and low birth weight,12 although other studies found no significant associations with these outcomes.13–17 As a recent review of vitamin D and pregnancy outcomes concluded, the
quality of evidence was low.18 To date, no consensus exists regarding optimal vitamin D level in pregnancy. The objective of this present large prospective observational study was to assess maternal vitamin D status in Chinese pregnant women and its association with pregnancy outcomes, and thus provide evidence for clinical recommendations regarding vitamin D supplementation and potential screening in the care of pregnancy. MATERIALS AND METHODS Study population In the present study, participants were recruited in Guangzhou city (located 23.1ºN) between September 2010 and August 2011, which followed up to 2012. All pregnant women during this period visiting our hospital were invited to take part. The response rate was 96.1% (n = 2960). One hundred non-pregnant healthy women matched by age were randomly selected from February to March 2012 to establish a reference range of vitamin D status for healthy women living in the area, as there is
1 Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, People’s Republic of China; 2Department of Endocrinology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 108 Yanjiangxi Road, Guangzhou, People’s Republic of China; 3Department of Geriatrics, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, People’s Republic of China; 4Department of Laboratory, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, People’s Republic of China and 5Department of Obstetrics, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, People’s Republic of China. Correspondence: Dr H Xiao or Dr Z Wang, Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou 510080, People’s Republic of China. E-mail: [email protected] or [email protected] 6 These authors contributed equally to this work. Received 19 July 2013; revised 10 April 2014; accepted 13 April 2014
Vitamin D status and pregnancy outcomes J Zhou et al
2 no general consensus on the optimal 25OHD level for pregnant women. The use of vitamin D and calcium supplements were recorded. The pregnant women, if met inclusion and exclusion criteria, were enrolled in further analysis for pregnancy outcomes (n = 1953). They were evaluated and data were recorded at antenatal cares (clinical characteristics were recorded at first antenatal care) and after delivery. Written informed
Figure 1.
consent and approval were obtained from all subjects and the institutional ethical committee (Figure 1).
Criteria for patient eligibility Inclusion criteria: a, age ⩾ 18 years; b, delivery (including the normal delivery, abortion, induced labor) in our hospital.
Study profile.
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Vitamin D status and pregnancy outcomes J Zhou et al
3 Exclusion criteria: a Lack of informed consent; b Increased liver enzymes by a factor of two or more above upper normal limits; c Chronic disease and tumor; d Before 13 weeks of gestation, including 13 weeks, pregnant women are accompanied by severe infections, trauma or in perioperative; e Before 13 weeks of gestation, including 13 weeks, pregnant women take corticosteroids, drug abuse (including alcohol).
Categorization Based on the 25OHD level, we categorize the pregnant women into three groups: (1) group A (low level) (⩽20 ng/ml), (2) group B (medium level) (21–29 ng/ml) and (3) group C (high level) (⩾30 ng/ml), according to reference values for an adult population.19,20
Definition of seasons and temperature Seasons of sample collection were defined as winter (December, January, February), spring (March, April, May), summer (June, July, August) and fall (September, October, November). Data of temperature were obtained from the Meteorological Bureau of Guangdong province.
Measurement Maternal blood was collected in the non-fasting condition at 16–20-week gestation. Serum were stored at − 70°C until they were analyzed for 25(OH)D. Serum 25(OH)D was assayed by using electrochemiluminescence immunoassay (Roche Diagnostics, Mannheim, Germany). The assay correlated well with liquid chromatography–tandem mass spectrometry and high-performance liquid chromatography.21 The elecsys assay recognized only 25(OH) D. The assay has a sensitivity of 4 ng/ml, an intraand inter-assay coefficient of variation of 6.6% and 5.4%, respectively. None of the values were below the lower limit of detection. Serum total calcium, albumin and inorganic phosphorus were analyzed spectrophotometrically (Sigma Diagnostics, St Louis, MO, USA).
Pregnancy outcomes The following pregnancy outcomes were recorded. (1) Maternal outcomes: premature rupture of membranes break (when the membranes that hold the amniotic fluid break too early), gestational diabetes (all women undergo a 75-g oral glucose tolerance test at 24–28 weeks of gestation, the diagnosis of gestational diabetes is made when any of the following plasma glucose values are exceeded: fasting: ⩾ 92 mg/dl,1 h: ⩾ 180 mg/dl, 2 h: ⩾ 153 mg/dl), polyhydramnios (a state where liquor amnii exceeds 2000 ml), oligohydramnios (a state where liquor amnii less than 300 ml in the third trimester of pregnancy), pre-eclampsia (pre-eclampsia is defined as high blood pressure and excess protein in the urine after 20 weeks of pregnancy in a woman who previously had normal blood pressure), cesarean section, preterm delivery (a live birth before 37 completed weeks of gestation). (2) Fetal outcomes: spontaneous abortion (fetal loss after enrollment but before 20 completed weeks of gestation), medically induced labor (termination of pregnancy because of serious maternal or fetal risks), fetal death (intrauterine fetal demise after 20 completed weeks of
Table 1.
gestation), fetal distress (defined as depletion of oxygen and accumulation of carbon dioxide, leading to a state of ‘hypoxia and acidosis’ during intra-uterine life. Baseline fetal heart rate o 110 bpm, sustained >5 min; late deceleration without variability; fetal heart rate 110–160 bpm without variability and accelerations), fetal growth restriction (deviation in expected fetal growth pattern (10th percentile), measuring height of the upper portion of the uterus and evaluate the growth of the baby by ultrasound). (3) Neonatal outcomes: malformations (including nervous system, circulatory system, digestive system, reproductive system, urinary system, musculoskeletal, chromosome disorder and others), birth weight and height, low birth weight (o2500 g), macrosomia (>4000 g), small-forgestational-age (weight o10th percentile or 2SD at birth), score of Apgar 1′,5′, asphyxia of newborn (a failure to start regular respiration within a minute of birth).
Statistical analysis SPSS software (version 17.0; SPSS, Chicago, IL, USA) was used for all statistical calculations. Values are presented as means ± s.d. or mean (95% confidence interval (CI)) for variables with normal distribution. Comparisons of normally distributed value among more than two groups were performed with analysis of variance (one-way analysis of variance test). Proportion was compared by using the χ2 test. Correlations were studied by using Pearson’s correlation coefficient. Logistic regression analysis was used to assess the associations between different levels of vitamin D and pregnancy outcomes after adjusting for relevant confounding factors (maternal age, systolic/diastolic pressure, prepregnancy body mass index (BMI) and serum calcium). A P-value of 0.05 defined statistical significance.
RESULTS Of 3080 pregnant womsen visited the hospital, 96.1% (n = 2960) took part in; furthermore, 63.4% (n = 1953) met inclusion criteria and were enrolled in further analysis for pregnancy outcomes. Characteristics of pregnant women At baseline, pregnant women in high level group were significantly older than the women in low and medium level groups (mean age, 30.3 ± 3.9 years vs 29.2 ± 3.5 years and 29.5 ± 3.6 years; P o0.01) and had a marginally higher prepregnancy BMI (mean, 20.67 ± 2.64 vs 20.28 ± 2.52 and 20.24 ± 2.51 kg/m2, respectively; P = 0.05). Systolic and diastolic pressure and percentage of regular vitamin D supplementation were not significantly different among the three groups (Table 1). Vitamin D status in pregnant women Mean serum 25(OH)D in all pregnant women was 27.03 ± 7.92 ng/ml (n = 2960). 25(OH)D in low, medium and high level groups were 16.59 ± 2.6, 24.87 ± 2.79 and 35.88 ± 5.2 ng/ml, respectively (Table 1). In total, 18.9% (n = 559) and 48.6% (n = 1438) of pregnant women had low level and medium level of vitamin D, respectively. There were only 16 (0.54%) pregnant women who had a 25(OH)D over 50 ng/ml. Non-pregnant healthy women (n = 100) matched by age (29.50 ± 3.94 vs 29.43 ± 2.92, P = 0.895) had a lower level of 25(OH)D (18.22 vs 27.03 ng/ml,
Clinical characteristics of pregnant women at 16–20-week gestation (n = 1953)
25-hydroxyvitamin D (ng/ml) Age (year) Systolic pressure (mmHg) Diastolic pressure (mmHg) Prepregnancy body mass index (kg/m2) Regular vitamin D supplementa (%)
Group A
Group B
Group C
P-value
16.59 ± 2.60 29.2 ± 3.5 119.2 ± 10.8 72.1 ± 9.4 20.28 ± 2.52 72.5
24.87 ± 2.79 29.5 ± 3.6 119.3 ± 11.1 73.7 ± 24.5 20.44 ± 2.51 73.4
35.88 ± 5.20 30.3 ± 3.9 119.4 ± 11.2 72.5 ± 8.5 20.67 ± 2.64 73.5
o0.01 o0.01 0.924 0.277 0.050 0.356
Defined as Vitamin D3 ⩾ 500 IU per day more than 3 days per week.
a
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Vitamin D status and pregnancy outcomes J Zhou et al
4 Po 0.001) and higher prevalence of low level of vitamin D than pregnant women (71.0% vs 18.9%, P o 0.001). There was seasonal variation in serum 25(OH)D concentration. Maternal 25(OH)D was highest in summer (28.52 ± 7.93 ng/ml, n = 745) and lowest in winter (24.99 ± 7.50 ng/ml, n = 664) (P o 0.001). The prevalence of low level of vitamin D was 14.2% in summer and 26.2% in winter (Table 2). 25(OH)D level in pregnant women was positively correlated with temperature (R = 0.942, R2 = 0.877, P o0.001) as shown by linear regression analysis. The regression equation was: 25(OH) D = (0.214 × T)+22.386. Serum 25(OH)D levels in pregnant women were positively correlated with serum calcium as well (R = 0.074, R2 = 0.005, P = 0.001). Serum calcium concentration in high level group was 2.23 ± 0.14 mmol/l, which was higher than that in low level (2.20 ± 0.12 mmol/l) and medium level group (2.21 ± 0.13 mmol/l) (P = 0.005). The regression equation was: Ca = 2.178 × 25(OH)D) +22.386 Association of vitamin D status and pregnancy outcomes Most maternal outcomes (premature rupture of membranes break, polyhydramnios, oligohydramnios, pre-eclampsia, cesarean
Table 2.
DISCUSSION In this large single center prospective observational study, unexpected high prevalence of low level of vitamin D was demonstrated in pregnant women at 16–20-week gestation who are living in a tropical region with abundant sunshine and regular
Percentage of vitamin D status in pregnant women at 16–20-week gestation in different seasons Winter
Low level Medium level High level
Table 3.
section) were not significantly different between the three groups. There were also no significant differences in fetal (spontaneous abortions, medically induced labor, fetal death, fetal distress, fetal growth restriction) and neonatal outcomes (malformations, birth weight and height, low birth weight, macrosomia, small-forgestational age, score of Apgar 1′,5′, asphyxia of newborn) between groups. Prevalence of gestational diabetes and preterm delivery in high level group (20.25% and 10.53%) was higher than that in low (12.97% and 6.04%) and medium level group (16.28% and 7.62%) (Table 3). Significant associations were also found between vitamin D status and gestational diabetes and preterm delivery (adjusted odds ratio (OR) 1.017, 1.039, respectively) (Table 4). However, there was no significant association between other pregnancy outcomes with different levels of vitamin D at 16–20-week gestation (Table 4).
Spring
Summer
Fall
n
%
n
%
n
%
n
%
174 336 154
26.2 50.6 23.2
161 400 254
19.8 49.1 31.2
106 335 304
14.2 45.0 40.8
118 367 260
15.8 49.3 34.9
Outcomes of pregnant women, fetuses and live births grouped according to vitamin D status
Pregnancy outcomes
Group A
Group B
P-value
Group C
n
%
n
%
n
%
Maternal outcomes Premature rupture of membranes break Gestational diabetes Polyhydramnios Oligohydramnios Pre-eclampsia Cesarean section Preterm delivery
370 77 48 13 8 13 200 22
20.81 12.97 3.51 2.16 3.51 55.10 6.04
946 215 154 37 15 36 547 71
22.73 16.28 3.91 1.59 3.81 58.57 7.62
637 134 129 31 14 25 380 66
21.04 20.25 4.87 2.20 3.92 60.51 10.53
0.425 0.099 0.173 0.421 0.900 0.220 0.052
Fetal outcomes Spontaneous abortion Medically induced labor Fetal death Fetal growth restriction
364 1 5 3 3
0.27 1.37 0.82 0.82
932 6 8 4 5
0.64 0.86 0.43 0.54
627 2 8 7 10
0.32 1.28 1.12 1.59
0.813 0.207 0.058 0.337
Neonatal outcomes Malformations Birth height (cm) Birth weight (kg) Low birth weight Macrosomia Small-for-gestational-age infants Apgar 1′ Apgar 5′ Asphyxia of newborn
364 13
3.57
932 37
3.97
627 22
3.51 49.2 ± 2.9 3.141 ± 0.484 12 1.91 17 2.71 4 0.64 9.83 ± 0.75 9.96 ± 0.43 14 2.23
0.779 0.053 0.461 0.647 0.458 0.793 0.673 0.497 0.421
49.5 ± 1.9 3.138 ± 0.434 11 3.02 6 1.65 4 1.10 9.81 ± 0.73 9.98 ± 0.22 4 1.10
49.4 ± 2.1 3.166 ± 0.471 10 1.07 22 2.36 3 0.32 9.82 ± 0.66 9.97 ± 0.30 18 1.93
Data expressed as mean ± s.d., number (sum of subgroup) or %. P-values when comparing low level Group A and medium level Group B with high level Group C (used logistic regression analysis).
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Vitamin D status and pregnancy outcomes J Zhou et al
5 Table 4.
Associations between pregnancy outcomes and vitamin D status by multiple regression analysis (n = 1953) Odds ratio
Lower of 95% confidence interval for odds ratio
Upper of 95% confidence interval for odds ratio
P-value
Maternal outcomes Premature rupture of membranes break Gestational diabetes Polyhydramnios Oligohydramnios Pre-eclampsia Cesarean section Preterm delivery
0.997 1.017 1.027 1.011 1.003 1.003 1.039
0.983 1.001 0.999 0.970 0.965 0.990 1.018
1.011 1.033 1.056 1.054 1.043 1.015 1.060
0.642 0.034 0.059 0.609 0.872 0.671 0.000
Fetal outcomes Spontaneous abortion Medically induced labor Fetal death Fetal distress Fetal growth restriction
1.036 1.016 1.023 0.995 1.036
0.949 0.959 0.958 0.978 0.983
1.132 1.076 1.094 1.013 1.092
0.429 0.598 0.497 0.601 0.190
Neonatal outcomes Malformations Low birth weight Macrosomia Small-for-gestational-age infants Asphyxia of newborn
1.016 1.016 1.010 0.988 1.032
0.984 0.972 0.972 0.916 0.991
1.049 1.061 1.051 1.067 1.074
0.338 0.486 0.603 0.762 0.128
Pregnancy outcomes
Logistic regression analysis. Odds ratio for associations between pregnancy outcomes and vitamin D status. Odds ratio adjusted for maternal age, systolic/ diastolic pressure, prepregnancy body mass index and serum calcium.
use of prenatal vitamin D. 25(OH)D was highest in summer and lowest in winter, and was positively correlated with the average temperature of the month. No associations were observed between maternal 25(OH)D status and majority of adverse pregnancy outcomes except for higher prevalence of gestational diabetes and preterm delivery in women with high level vitamin D. Hypovitaminosis D is a significant problem in China and across the globe. Two cross-sectional studies with small sample sizes conducted in Shanghai22 (located 31.1ºN) and Chengdu23 (located 30.7ºN) found that 69% and 57.1% of pregnant women had vitamin D deficiency with mean levels of 17.57 ± 11.44 ng/ml and 14.38 ± 7.88 ng/ml, respectively. Our present study demonstrated high prevalence of low (18.9%) level of vitamin D in Chinese pregnant women living in Guangzhou, although it is lower than that in Shanghai and Chengdu. Our data showed that pregnant women living in Guangzhou (located 23.1ºN) had higher mean serum 25(OH)D level (27.03 ± 7.92 ng/ml) than those living in Shanghai and Chengdu, two cities locating at higher latitude. Higher latitude might relate to less vitamin D production in the skin. Regular use of prenatal vitamin D (over 70%) in our study population might be another contributor to higher vitamin D level in pregnant women living in Guangzhou. Seasonal variation in 25(OH)D status was observed in American,4 Australian (22)24 and Indian25 pregnant women. Similar observation was found in our study which showed a strong positive correlation between serum 25(OH)D level and the average temperature of the month. Highest maternal serum 25(OH)D level in summer and lowest in winter was evidenced in this study. Despite growing interest in the relationships between vitamin D status during pregnancy and maternal and neonatal outcomes, the results of previous reports are inconsistent. Most recently, a systematic review suggested protective effects of vitamin D supplementation on low birth weight (risk ratio = 0.40 (95% CI 0.23, 0.71)) and non-significant but suggestive effects of daily supplementation on small-for-gestational age (risk ratio = 0.67 (0.40, 1.11)),18 while another meta-analysis performed by Rabi DM26 found insufficient serum levels of 25-OHD were associated © 2014 Macmillan Publishers Limited
with gestational diabetes (pooled OR 1.49, 95% CI 1.18–1.89), preeclampsia (1.79, 1.25–2.58) and small-for-gestational age infants. In our present study, there were no significant differences in most adverse pregnancy outcomes among pregnant women with different levels of vitamin D at 16–20-week gestation. To our surprise, our study showed that prevalence of gestational diabetes (adjusted OR 1.017; 95% CI 1.001–1.033) and preterm delivery (adjusted OR 1.039; 95% CI 1.018–1.060) in high level group was higher than that in low and medium level groups. In experimental studies, vitamin D is thought to have both direct (through activation of vitamin D receptor ) and indirect (via regulation of calcium homeostasis) effects on various mechanisms related to the pathophysiology of diabetes including pancreatic β-cell dysfunction, impaired insulin action and systemic inflammation.27 In our study, pregnant women in high level group were older and had slightly higher prepregnant BMI than those in low and medium level groups. Older age and higher BMI are traditional risk factors for gestational diabetes and might contribute to higher prevalence of gestational diabetes in pregnant women with high level of vitamin D in our findings. Other risk factors such as smoking, alcohol, gestational weight gain, socio-economic status may also contribute. Future well-designed randomized clinical trials are required to elucidate whether vitamin D supplementation might interfere with glucose metabolism in pregnancy. Until now, there are limited observational data available on the relationship of vitamin D and preterm delivery. In an observational study, gestation length was 0.7 week shorter in infants of 27 mothers with low 25(OH)D (o 28 nmol/l) at 28–32 week vs babies whose mothers had higher concentrations.28 In another nested case-control study with women with prior spontaneous preterm birth, serum 25(OH)D concentration was not associated with preterm birth.13 More intervention and observational studies are needed to assess the potential for vitamin D to influence the risk of preterm delivery. Our study was limited by lack of data on sunlight exposure, dietary vitamin D intake, measurement of 25(OH)D from cord blood and infants in late pregnancy and those who were not delivered in our hospital. Low prevalence of some pregnancy European Journal of Clinical Nutrition (2014) 1 – 6
Vitamin D status and pregnancy outcomes J Zhou et al
6 outcomes may cause false negative results. The relationships between vitamin D status in pregnant women and neonatal/ infants’ growth and health outcomes have not been observed as well in this study. There are reports that low vitamin D status of pregnant mothers could be related to adverse health outcomes in the offspring.29,30 A long follow-up study is imperative to confirm this observation, and observe long-term effects of vitamin D on women and infants. Our study is a large prospective observational study evaluating vitamin D level and its association with pregnancy outcomes, with a sample size of 1953 pregnant participants. Many pregnancy outcomes were evaluated in our study, such as premature rupture of membranes break, fetal growth restriction, malformations, macrosomia and asphyxia of newborn, have not been reported previously. New evidence concerning the association between vitamin D level and pregnancy outcomes was demonstrated in our study. This large prospective observational study showed a high prevalence of low level of vitamin D among pregnant women in southern China who are thought to have sufficient exposure to ultraviolet B radiation and who are on regular use of prenatal vitamin D supplement. There were no significant differences in most adverse pregnancy outcomes among pregnant women with different levels of vitamin D at 16–20-week gestation except for higher prevalence of gestational diabetes and preterm delivery in women with high level of vitamin D, possibly related to the older age and higher BMI of this group. More well-designed randomized prospective clinical trials of vitamin D supplement during pregnancy are needed to evaluate the potential role of vitamin D to prevent adverse outcomes. CONFLICT OF INTEREST The authors declare no conflict of interest.
AUTHOR CONTRIBUTIONS JZ performed experiments, analysed data and wrote the paper. LS searched literature, analysed data and wrote the paper. JZ and LS contributed equally to this work. ML was involved in performing the 25(OH)D measurements. YL and XC interpretated data. ZW was involved in patient care and data collection. HX designed the study and wrote the paper.
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