Journal of Perinatology (2014) 34, 767–773 © 2014 Nature America, Inc. All rights reserved 0743-8346/14 www.nature.com/jp
ORIGINAL ARTICLE
Vitamin D deficiency in pregnant women of ethnic minority: a potential contributor to preeclampsia IV Reeves1, ZD Bamji2, GB Rosario1, KM Lewis3, MA Young1 and KN Washington2 OBJECTIVE: We investigated risk for comorbidities and preeclampsia at low vitamin D levels in ethnic minorities. STUDY DESIGN: Umbilical cord vitamin D (25(OH)D) concentration was determined in urban minorities: 80.9% African American and 17% Hispanic mothers-baby pairs. To identify the correlation between vitamin D levels and high-risk comorbidities which result in preeclampsia, multivariate logistic regression analyses were performed. RESULT: Below the Institute of Medicine threshold of 25(OH)D for pregnant women (25 ng ml− 1), obesity (P = 0.055) and pregestational diabetes (odds ratio (OR) = 2.056) were observed. The study median was 16 ng ml − 1 (o 25th percentile), at which gestational hypertension (P = 0.042), chronic hypertension (OR = 4.842) and pregestational diabetes (OR = 3.45) became relevant. The risk for preeclampsia increased 12-fold with gestational hypertension (P = 0.003) and 14-fold with combined chronic and gestational hypertension (P = 0.001). CONCLUSION: Pregnant women of ethnic minority had lower median vitamin D levels which may contribute to a potential risk for preeclampsia. Journal of Perinatology (2014) 34, 767–773; doi:10.1038/jp.2014.91; published online 22 May 2014
INTRODUCTION Vitamin D is a pleiotropic pro-hormone that regulates a large number of human genes via receptors,1–4 including those on the human placenta.2 Vitamin D deficiency is extremely common even in developed societies, especially during pregnancy.5,6 Data from the US National Health and Nutrition Examination Survey (NHANES 2001 to 2006) revealed that vitamin D deficiency is present in 80% African American and 13% White American women of reproductive age. The Institute of Medicine (IOM) reports the Vitamin D threshold for pregnant and lactating women at the 50th percentile is 25 ng ml − 1 (62.4 nmol l − 1).7 During pregnancy, calcium demand increases toward the third trimester because of increasing fetal requirements for bone mineral accretion.8 Fetal and newborn vitamin D status is dependent on that of the mother;3,9,10 thus, maternal vitamin D status is important.3,5,9,11 Vitamin D deficiency in pregnancy is well recognized by the CDC (Center for Disease Control) and ACOG (American College of Obstetrics and Gynecology); however, there is no clear consensus for screening and management due to lack of research data that provides the optimal and safe supplementation.12,13 A pool of evidence relating to the clinical outcomes of vitamin D deficiency in pregnancy is accumulating. Johnson et al.14 reported that in pregnant women, despite living in southern latitudes in the United States, the prevalence of vitamin D disparity was higher in African Americans (97%) compared with Hispanics (81%) and Caucasians (67%). Jackson et al.15 reported that minorities suffer disproportionately (threefold) from perinatal complications due to vitamin D deficiency, which can be associated with a higher risk for pregnancy-related death as compared with whites, and 1
a high prevalence (16%) of pregnancy-induced hypertension (preeclampsia).16–18 The risk of serious complications from preeclampsia is also associated with neonatal morbidity, death, preterm delivery19 and other health conditions10,20,21 that could extend into adulthood.1,2,22–24 In addition, women with no prenatal care had a higher risk of death from preeclampsia or eclampsia than those who had some level of prenatal care.17 Pregnant minorities have been least studied in vitamin D-associated diseases25 despite commonly presenting with any single or combination of high risk comorbidities (that is, obesity, diabetes, hypertension, asthma, limited prenatal care, and low-birthweight infants) associated with poor pregnancy outcomes.3,25,26 This study was designed to investigate the prevalence of vitamin D deficiency in a cohort of pregnant ethnic minorities and analyze association(s) between lower serum 25(OH)D concentration and pregnancy-related comorbidities including neonatal outcomes.
METHODS After approval by the Institutional Review Board at Howard University, this study was conducted from June to September 2012 in Washington, DC to optimize environmental parameters of sunlight exposure. Blood samples were collected from detached umbilical cord immediately following delivery of the infant. Each mother–baby pair was considered one study subject, to include multiple births. Participants were included on the basis of the following criteria: (1) All delivering pregnant female regardless of a history of prenatal care, race or ethnicity, and (2) Provision of written informed consent from the mother. Participants were excluded if: (1) known disorder of parathyroid, calcium or magnesium metabolism, chronic renal disease/failure or uncontrolled thyroid disease, (2) use of
Division of Neonatology, Department of Pediatrics and Child Health, The Howard University College of Medicine and the Howard University Hospital, Washington, DC, USA; Department of Pediatrics and Child Health, Human Genetics, The Howard University College of Medicine and the Howard University Hospital, Washington, DC, USA and 3 Department of Obstetrics and Gynecology, The Howard University College of Medicine and the Howard University Hospital, Washington, DC, USA. Correspondence: Dr IV Reeves, Division of Neonatology, Department of Pediatrics and Child Health, The Howard University College of Medicine and the Howard University Hospital, 2041 Georgia Avenue NW, Washington, DC 20060, USA. E-mail: [email protected] Received 14 November 2013; revised 2 April 2014; accepted 4 April 2014; published online 22 May 2014 2
Vitamin D deficiency, a potential contributor to preeclampsia IV Reeves et al
768 Table 1.
Descriptive characteristics of the study group
Descriptive characteristics Mothers (N = 47) Age (years) Vitamin D level (ng ml − 1) Gravida Parity Time of onset of prenatal care (weeks) Number of prenatal visits Prepregnancy BMI Infants (N = 49) Gestational age (weeks) Birth weight (g) Birth length (cm) Ponderal index (PI) Birth head circumference (cm) Ionized Ca+2 level (mg dl − 1)
Median
Mean
s.e.m.
s.d.
26.00 16.00 3.00 1.00 12.00 7.00 29.60
27.28 17.51 3.55 1.53 16.45 7.60 31.15
1.01 1.15 0.34 0.27 1.28 0.50 1.20
6.95 7.90 2.31 1.84 8.78 3.43 8.21
38.60 2975.00 48.00 2.59 33.50 5.90
37.94 2947.43 47.78 2.67 33.33 5.87
0.35 97.57 0.44 0.05 0.26 0.06
2.42 683.00 3.06 0.32 1.85 0.43
Range 17.00–40.00 5.00–43.00 1.00–10.00 0.00–7.00 5.50–38.40 0.00–18.00 18.90–59.60 31.00–41.00 1735.00–4710.00 42.00–54.00 2.18–3.39 29.00–37.00 4.80–7.20
Abbreviation: BMI, body mass index. Vitamin D levels (conversion: nmol l − 1 divided by 2.5 = ng ml − 1).
anticonvulsants or rifampicin, (3) congenital or family history of bone disorder, and (4) newborn with congenital anomaly. In total, forty-eight mothers were recruited and fifty infant samples were collected; this population included two sets of twins. One mother–baby pair was eliminated on the basis of diagnosed Down’s syndrome following delivery. Prepregnancy body mass index (BMI) was obtained from self-reports or from the prenatal record.
Sample processing Umbilical cord blood was collected in a serum-separator tube (gold top), specimen was de-identified by the study coordinator, coded and sent for determination of serum 25(OH)D and ionized calcium. Laboratory personnel were blinded to all patient identification and medical data. For measurement of 25(OH)D concentration, 3 ml of cord blood sample was immediately processed at Howard University Hospital Clinical Laboratory and transported for analysis to the Nichols Institute Diagnostics, Chantilly, VA, USA. This analysis was by liquid chromatography, tandem mass spectrometry method that employed extraction via protein precipitation with 100% specificity (gold standard) with measuring range of 4 to 100 ng ml − 1 (10 to 260 nM). Ionized calcium concentration was similarly transported and measured using an ion specific electrode method within 24 h of collection of 4 ml of cord blood. This analysis is empirically based on a measured pH and ionized calcium concentration normalized to a pH 7.40.
Statistical analyses Means, medians and standard deviations were calculated for anthropomorphic and physiologic characteristics. Participants were classified as IOM threshold (⩾25 ng ml − 1) or low ( o25 ng ml − 1) based on vitamin D blood concentrations as defined by the IOM 50th percentile for pregnant and lactating women. The t-tests were performed to determine if vitamin D blood levels altered anthropomorphic and physiologic characteristics in mothers and their infants. Bivariate (Fisher’s exact test) and multivariate (Multi-nominal Logistic Regression Analysis) were performed to determine the association between the comorbidities and vitamin D levels (IOM threshold or low) and potentiating factors for preeclampsia. The odds ratios and 95% confidence intervals were calculated for comorbidities and risk factors for preeclampsia. All statistical analyses were performed using SPSS version 20 (SPSS, Chicago, IL, USA).
RESULTS The clinical utility and accuracy of cord blood sampling is justified on the basis of previous studies demonstrating that maternal serum and cord blood levels of 25(OH)D are closely correlated (r = 0.95, P o 0.0001).26–30 Serum concentration of 25(OH)D is an established biomarker of vitamin D status.27,30,31 Journal of Perinatology (2014), 767 – 773
Mother and infant characteristics are described in Table 1. Our study population had a median cord vitamin D concentration of 16 ng ml − 1, which is substantially below the 25th percentile by IOM.28 Notably, our gestational ages were in the third trimester and the median prepregnancy BMI of 29.6 indicated an overweight group (18.9 to 59.6; obese ⩾ 30 by CDC definition). In Table 2, 85.1% (40/47) of our cohort were significantly below the IOM threshold (P = 0.001). Women who entered prenatal care in the first trimester had vitamin D concentrations closer to threshold. Ionized calcium concentrations were unchanged regardless of vitamin D levels. Demographically, our cohort consisted of 80.9% African American, 17% Hispanics and 2.1% Caucasian (Table 3). Intergroup differences between ethnicities approached statistical significance (P = 0.062) for low vitamin D. The incidence of low vitamin D was seen in 89.47% (34/38) of African Americans. Our cohort showed 80.9% women were o 35 years of age, of which 89.47% (34/38) were below the IOM threshold (P = 0.087). The BMI of 48.9% women was ⩾ 30; 95.65% (22/23) of which were below the IOM threshold (P = 0.055). A threefold increase in pregestational diabetes at low vitamin D levels was observed. All cases with chronic hypertension (10.6%) had low vitamin D levels. Table 4 describes the association of selected comorbidities with the risk of developing preeclampsia. There were no direct associations between low 25(OH)D levels and risk for preeclampsia. Gestational diabetes alone was associated with a twofold risk for preeclampsia. Two statistically significant associations were observed: (1) gestational hypertension increased the risk for preeclampsia by 12-fold (OR = 12.375; CI = 2.4 to 63.558, P = 0.003) and (2) the combination of chronic and gestational hypertension increased the risk for preeclampsia by 14-fold (OR = 14.5; CI = 2.555 to 82.278, P = 0.001; Figure 1). DISCUSSION A disproportionate cohort of women with low vitamin D was observed, where 85.1% were below the IOM threshold in pregnancy. This cohort remained deficient despite the study occurring during the months of maximum sunlight exposure and the utilization of prenatal vitamin supplements (78.7% deficient (37/47, not shown in charts)). In a study conducted by Bodnar et al.,32 prenatal Vitamin D supplementation at 400 IU/day in 90% of mothers also did not prevent deficiency. Below the IOM threshold, maternal age (o 35 years), prepregnancy BMI ⩾ 30 © 2014 Nature America, Inc.
Vitamin D deficiency, a potential contributor to preeclampsia IV Reeves et al
7.46 2.63 2.01 9.72 9.59 2.32 797.82 3.35 0.31 2.13 0.33 28.35 2.52 1.43 30.58 17.98 38.10 3052.04 48.21 2.67 33.35 5.96 6.40 2.02 1.66 6.63 7.85 2.59 549.13 2.74 0.34 1.56 0.50 0.685 0.343 0.949 0.978 0.001 0.922 0.145 0.118 0.647 0.144 0.730 − 1.498 − 0.550 0.159 2.175 2.104 1.604 0.108 0.151 0.407 1.068 0.019 0.167 0.919 0.005 0.001 12.161 0.010 2.195 2.535 0.212 2.203 0.121 30.86 4.00 1.43 25.16 10.23 36.69 2921.43 47.61 2.62 32.64 5.87
7.86 1.83 1.81 9.17 1.72 2.81 1004.94 4.18 0.34 2.66 0.47
Low vitamin D and diabetic conditions of pregnancy Vitamin D receptors are present on pancreatic β cells and 1,25 (OH)2D3 is essential for normal insulin release.34 Additional studies have demonstrated prevalence of vitamin D deficiency in type 1 diabetes; and vitamin D supplementation during pregnancy or infancy improves glycemic control.35 Low threshold of vitamin D deficiency increases risk factors for insulin resistance and glucose intolerance,36,37 thereby increasing risk of gestational diabetes in pregnancy.38 No statistical significance for pregestational or gestational diabetes was observed; however, there was a threefold increased risk in the pregestational diabetic cohort below the IOM threshold. This remains an active area of research as critical vitamin D deficiency could be a modifiable risk factor for glucose control during pregnancy.
6.69 2.40 1.87 7.69 9.08 2.32 631.04 2.89 0.32 1.69 0.42
© 2014 Nature America, Inc.
Abbreviation: BMI, body mass index.
Age (years) Gravida Parity Prepregnancy BMI Time of onset of prenatal care (weeks) Gestational age at birth (weeks) Birth weight (g) Birth length (cm) Ponderal index (PI) Birth head circumference (cm) Ionized Ca+2 level (mg dl − 1)
40 40 40 40 40 40 42 42 42 42 37
26.65 3.47 1.55 32.20 17.53 38.26 2951.76 47.80 2.67 33.45 5.87
7 7 7 7 7 7 7 7 7 7 6
s.d. Mean n s.d. Mean n
Vitamin D o25
Low vitamin D and prepregnancy BMI Scholl et al.33 showed, in a large Camden population study involving 2251 pregnancies, that total vitamin D intake correlated inversely with BMI. Bodnar et al.26 established the relationship of prepregnancy BMI to vitamin D deficiency, reporting that there was a higher prevalence of overweight and obese pregnant women among non-Hispanic black women compared with white women (P o 0.01). After confounder adjustment, a 10 kg m −2 increase in maternal BMI was associated with lower concentrations of serum 25(OH)D.32 Similarly, this study showed that lower 25(OH)D levels below IOM threshold were associated with obesity.
24 24 24 24 24 24 25 25 25 25 22
26.25 3.58 1.63 31.69 14.97 37.96 2847.00 47.36 2.66 33.31 5.79
23 23 23 23 23 23 24 24 24 24 21
s.d. Mean s.d. Mean n
Vitamin D o16 P-value t F Vitamin D ⩾ 25
IOM standards Comparisons of anthropomorphic and physiologic characteristics
Table 2.
Comparisons of anthropomorphic and physiologic characteristics with vitamin D level at IOM standards and study group median
n
Vitamin D ⩾ 16
Study group
F
1.604 2.238 0.566 1.150 2.529 1.655 1.123 0.416 0.207 1.744 1.819
t
− 1.036 0.090 0.351 0.459 − 1.180 − 0.191 − 1.052 − 0.976 − 0.086 − 0.083 − 1.327
0.212 0.142 0.456 0.289 0.119 0.205 0.295 0.522 0.651 0.193 0.185
P-value
769 (obesity), pregestational diabetes and chronic hypertension were comorbidities. The median vitamin D levels (16 ng ml − 1) were below the 25th percentile of IOM. It was hypothesized that in the minority population, the comorbidities at IOM threshold might not be apparent. In an attempt to address this concern, these data were further analyzed at the median vitamin D level (16 ng ml − 1) of the minority women in the study. At maternal ages less than 35 years, lower concentrations of 25(OH)D had a two times greater occurrence than minority women above the age of 35 years (Table 3). Also, the risk for pregestational diabetes almost doubled (OR = 3.450) and the risk for chronic hypertension increased by approximately fourfold (OR = 4.842). Gestational hypertension was more prevalent in minority women with low vitamin D levels below IOM (P = 0.042). These data suggested an underestimation of comorbidities at vitamin D below the IOM threshold (Figure 2). These investigations identified, not only high-risk pregnancy comorbidities at levels of vitamin D below the IOM threshold but also their possible association to potentiate preeclampsia. A comparative review of our study with that of other authors is as follows:
Low vitamin D and hypertensive conditions of pregnancy We used current definitions of gestational hypertension, chronic hypertension and preeclampsia.39 A recent study has shown that preeclampsia is seen at lower vitamin D levels.40 Vitamin D has important immunomodulating properties that may help to establish a proper maternal immune response to the placenta.2,32,41 It also regulates key target genes associated with proper implantation of the placenta that may influence fetal–placental development and function.42 Evidence linking lower levels of vitamin D in pregnancy to preeclampsia was reported in a Pittsburgh study that observed an inverse monotonic dose response relationship between 25(OH)D concentration in early pregnancy and preeclampsia: for every 20 ng ml − 1 decline in 25(OH)D levels, the risk of preeclampsia more than doubled.44 Similarly, a nested case control study from North Carolina reported that women with 25 (OH)D levels less than 20 ng ml − 1 had more than five times greater risk of severe preeclampsia than those with levels of Journal of Perinatology (2014), 767 – 773
770
Comorbid risk factors and their association with vitamin D thresholds (IOM 50th percentile>25 ng/ml and Study Group median> 16 ng/ml) during pregnancy
Comorbid factors associated by Vitamin D
A
B
Frequency of total
Vitamin D o25
Vitamin D o16
Vitamin D o25
Vitamin D ⩾ 25
Fisher’s exact
n (%)
Anova P-value
Anova P-value
n (%)
n (%)
P-value
26 (55.3) 14 (29.8)
5 (10.6) 2 (4.3)
0.553
C Odds ratio
95% Confidence interval
Vitamin D o16
Vitamin D ⩾ 16
Fisher’s exact
Lower
Upper
n (%)
n (%)
P-value
0.743
0.127
4.334
14 (29.8) 10 (21.3)
17 (36.2) 6 (12.8)
0.207
0.429
0.833
0.728
0.954
23 (48.9) 1 (2.1)
19 (40.4) 4 (8.5)
5 (10.6) 2 (4.3)
0.467
1.600
0.261
9.812
16 (34) 8 (17)
32 (68.1) 8 (17)
5 (10.6) 2 (4.3)
0.467
1.600
0.261
9.812
0.286
37 (78.7) 3 (6.4)
6 (12.8) 1 (2.1)
0.488
2.056
0.182
0.899
0.957
35 (74.5) 5 (10.6)
6 (12.8) 1 (2.1)
0.643
1.167
38 (80.9) 9 (19.1)
0.048
0.885
32 (68.1) 8 (17)
6 (12.8) 1 (2.1)
0.596
Obesity BMIo30 BMI ⩾30
24 (51.1) 23 (48.9)
0.730
0.667
18 (38.3) 22 (46.8)
6 (12.8) 1 (2.1)
Newborn gender Male Female
26 (55.3) 21 (44.7)
0.483
0.322
23 (48.9) 17 (36.2)
Mode of delivery Vaginal C-section
17 (36.2) 30 (63.8)
0.659
0.434
Gestational age o37 weeks ⩾ 37 weeks
11 (23.4) 36 (76.6)
0.196
Maternal age o35 years ⩾ 35 years
38 (80.9) 9 (19.1)
0.087
© 2014 Nature America, Inc.
Upper
0.494
0.144
1.699
0.160
4.842
0.498
47.056
21 (44.7) 2 (4.3)
0.042
0.190
0.035
1.022
20 (42.6) 4 (8.5)
17 (36.2) 6 (12.8)
0.333
1.765
0.426
7.307
23.162
23 (48.9) 1 (2.1)
20 (42.6) 2 (6.4)
0.280
3.450
0.332
35.857
0.115
11.814
21 (44.7) 3 (6.4)
20 (42.6) 3 (6.4)
0.646
1.050
0.189
5.826
0.667
0.070
6.353
20 (42.6) 4 (8.5)
18 (38.3) 5 (10.6)
0.471
1.389
0.322
5.986
0.055
0.136
0.015
1.239
12 (25.5) 12 (25.5)
12 (25.5) 11 (23.4)
0.557
0.917
0.292
2.879
3 (6.4) 4 (8.5)
0.377
1.804
0.356
9.142
15 (31.9) 9 (19.1)
11 (23.4) 12 (25.5)
0.237
1.818
0.568
5.817
15 (31.9) 25 (53.2)
2 (4.3) 5 (10.6)
0.501
1.500
0.258
8.722
10 (21.3) 14 (29.8)
7 (14.9) 16 (34)
0.310
1.633
0.490
5.437
0.351
8 (17) 32 (68.1)
3 (6.4) 4 (8.5)
0.197
0.333
0.062
1.798
7 (14.9) 17 (36.2)
4 (8.5) 19 (40.4)
0.272
1.956
0.486
7.867
0.246
34 (72.3) 6 (12.8)
4 (8.5) 3 (6.4)
0.117
4.250
0.753
23.981
21 (44.7) 3 (6.4)
17 (36.2) 6 (12.8)
0.209
2.471
0.537
11.368
0.632
5 (10.2) 26 (53.1) 11 (22.4)
1 (2.0) 3 (6.1) 3 (6.1)
4 (8.2) 15 (30.6) 6 (12.2)
2 (4.1) 14 (28.6) 8 (16.3)
0.311
34 (72.3) 1 (2.1) 5 (10.6)
4 (8.5) 0 3 (6.4)
21 (44.7) 0 3 (6.4)
17 (36.2) 1 (2.1) 5 (10.6)
0.747
Chronic hypertension (−) (+)
42 (89.4) 5 (10.6)
0.333
0.148
35 (74.5) 5 (10.6)
7 (14.9) 0
Gestational hypertension (−) (+)
37 (78.7) 10 (21.3)
0.618
0.040
32 (68.1) 8 (17)
Pregestational or gestational diabetes (−) 37 (78.7) (+) 10 (21.3)
0.618
0.441
Pregestational diabetes (−) (+)
43 (91.5) 4 (8.5)
0.563
Gestational diabetes (−) (+)
41 (87.2) 6 (12.8)
Asthma (−) (+)
Ethnicity African American Caucasian Hispanic
38 (80.9) 1 (2.1) 8 (17)
0.062
95% Confidence interval Lower
Chronic and gestational hypertension (− ) 31 (66) (+) 16 (34)
Birth weight (percentile adjusted for gestational age) Low (⩽25th) 6 (12.2) 0.629 Middle (>25 to o75th) 29 (59.2) High (⩾75th) 14 (28.6)
Odds ratio
(A) Frequency in study, ANOVA for Vitamin D of o25 ng/ml and o16 ng/ml, respectively. (B) Vitamin D levels cut off of 25 ng/ml and (C) Vitamin D levels cut off of 16 ng/ml. Statistical analysis using Fishers Exact test and Logistic regression for risk.
Vitamin D deficiency, a potential contributor to preeclampsia IV Reeves et al
Journal of Perinatology (2014), 767 – 773
Table 3.
Vitamin D deficiency, a potential contributor to preeclampsia IV Reeves et al
771 Table 4.
Comorbid factors as risk for preeclampsia
Comorbid factors contributing to preeclampsia
Preclampsia
Fisher's exact
Negative n (%)
Positive n (%)
P-value
Chronic and gestational hypertension (− ) (+)
29 (61.7) 8 (17)
2 (4.3) 8 (17)
0.001
Chronic hypertension (−) (+)
38 (72.3) 3 (6.4)
8 (17) 2 (4.3)
Gestational hypertension (−) (+)
33 (70.2) 4 (8.5)
Pregestational diabetes (−) (+)
Odd's ratio
95% Confidence interval Lower
Upper
14.500
2.555
82.278
0.285
2.833
0.404
19.873
4 (8.5) 6 (12.8)
0.003
12.375
2.409
63.558
34 (72.3) 3 (6.4)
9 (19.1) 1 (2.1)
0.630
1.259
0.117
13.599
Gestational diabetes (−) (+)
33 (70.2) 4 (8.5)
8 (17) 2 (4.3)
0.378
2.063
0.320
13.313
Asthma (−) (+)
29 (61.7) 8 (17)
9 (19.1) 1 (2.1)
0.375
0.403
0.044
3.669
Obesity BMI o30 BMI ⩾30
20 (42.6) 17 (36.2)
4 (8.5) 6 (12.8)
0.333
1.765
0.426
7.307
Gestational age o37 weeks ⩾ 37 weeks
7 (14.9) 30 (63.8)
4 (8.5) 6 (12.8)
0.164
0.350
0.077
1.583
Maternal age o35 years ⩾ 35 years
29 (61.7) 8 (17)
9 (19.1) 1 (2.1)
0.375
0.403
0.044
3.669
Vitamin D level of 25 (ng ml − 1) Vitamin D o25 Vitamin D ⩾ 25
31 (66) 6 (12.8)
9 (19.1) 1 (2.1)
0.533
0.574
0.061
5.410
Vitamin D level of 16 (ng ml − 1) Vitamin D o16 Vitamin D ⩾16
17 (36.2) 20 (42.6)
7 (14.9) 3 (6.4)
0.160
0.364
0.081
1.631
Statistics of Fisher's exact test and logistic regression for risk.
at least 30 ng ml − 1.45 Also, a large epidemiological study from Norway in nulliparous pregnant women showed a 27% reduction in risk of preeclampsia (OR = 0.73; CI = 0.58 to 0.92) with vitamin D supplementation of 10 to 15 μg dl − 1 as compared with no supplementation. All together, these findings support the hypothesis that maternal vitamin D deficiency may be an independent risk factor for preeclampsia.11 With regard to the timing of deficiency, a study in 274 nulliparous pregnant women showed that vitamin D deficiency at or before week 22 of gestation was an independent predictor of preeclampsia and low vitamin D status in the neonate. Patients with 25(OH)D levels at 15 ng ml − 1 had a fivefold increase in the risk of preeclampsia, despite receiving prenatal vitamins.44 Previous studies have shown that the incidence and severity of preeclampsia are multifactorial in associations with chronic hypertension46 and pregestational diabetes mellitus.46,47 This study revealed that both types of hypertension (chronic and/or © 2014 Nature America, Inc.
gestational) potentiated an increased risk for preeclampsia. In addition, Evensen et al.48 showed increased odds for preeclampsia with gestational diabetes. Vitamin D deficiency in the mode of delivery, gestational outcomes, growth parameters and serum ionized calcium. An observational study from Australia has shown no association between maternal 25(OH)D status with the mode of delivery and gestational ages; however, there was an association with low birth weight.49 Although African Americans are more likely to deliver low-birthweight infants,50 this was not seen in our infant cohort. The median growth parameters (weight, length, head circumference and PI) for gestational age were within the 50th percentile. When infant weights were adjusted for corresponding gestational age, there were no birth weight differences associated with lower vitamin D concentration. Although not statistically significant, Journal of Perinatology (2014), 767 – 773
Vitamin D deficiency, a potential contributor to preeclampsia IV Reeves et al
772 Association of Comorbidities with Preeclampsia
16.00
p=0.001
14.00 p=0.003
Odd's Ratio
12.00 10.00 8.00
CONCLUSION In these investigations, a cohort of ethnic minority pregnant women had vitamin D concentrations below the IOM median level, which appeared to contribute a substantial risk for preeclampsia. Vitamin D deficiency can be treated and, if therapeutic intervention occurs in early stages of gestation, could result in healthy pregnancy outcomes.
6.00
CONFLICT OF INTEREST
4.00
The authors declare no conflict of interest. 2.00
Vitamin D level of 16 (ng/mL)
Vitamin D level of 25 (ng/mL)
Maternal Age
Gestational age
Obseity
Asthma
Gestational Diabetes
Pregestational Diabetes
Gestational Hypertension
Chronic Hypertension
Chronic and Gestational Hypertension
0.00
Comorbidities contributing to Preeclampsia
Figure 1. Comparing odd ratios of preeclampsia to pregnancy comorbidities.
5.000 Vitamin D
ORIGINAL ARTICLE
Vitamin D deficiency in pregnant women of ethnic minority: a potential contributor to preeclampsia IV Reeves1, ZD Bamji2, GB Rosario1, KM Lewis3, MA Young1 and KN Washington2 OBJECTIVE: We investigated risk for comorbidities and preeclampsia at low vitamin D levels in ethnic minorities. STUDY DESIGN: Umbilical cord vitamin D (25(OH)D) concentration was determined in urban minorities: 80.9% African American and 17% Hispanic mothers-baby pairs. To identify the correlation between vitamin D levels and high-risk comorbidities which result in preeclampsia, multivariate logistic regression analyses were performed. RESULT: Below the Institute of Medicine threshold of 25(OH)D for pregnant women (25 ng ml− 1), obesity (P = 0.055) and pregestational diabetes (odds ratio (OR) = 2.056) were observed. The study median was 16 ng ml − 1 (o 25th percentile), at which gestational hypertension (P = 0.042), chronic hypertension (OR = 4.842) and pregestational diabetes (OR = 3.45) became relevant. The risk for preeclampsia increased 12-fold with gestational hypertension (P = 0.003) and 14-fold with combined chronic and gestational hypertension (P = 0.001). CONCLUSION: Pregnant women of ethnic minority had lower median vitamin D levels which may contribute to a potential risk for preeclampsia. Journal of Perinatology (2014) 34, 767–773; doi:10.1038/jp.2014.91; published online 22 May 2014
INTRODUCTION Vitamin D is a pleiotropic pro-hormone that regulates a large number of human genes via receptors,1–4 including those on the human placenta.2 Vitamin D deficiency is extremely common even in developed societies, especially during pregnancy.5,6 Data from the US National Health and Nutrition Examination Survey (NHANES 2001 to 2006) revealed that vitamin D deficiency is present in 80% African American and 13% White American women of reproductive age. The Institute of Medicine (IOM) reports the Vitamin D threshold for pregnant and lactating women at the 50th percentile is 25 ng ml − 1 (62.4 nmol l − 1).7 During pregnancy, calcium demand increases toward the third trimester because of increasing fetal requirements for bone mineral accretion.8 Fetal and newborn vitamin D status is dependent on that of the mother;3,9,10 thus, maternal vitamin D status is important.3,5,9,11 Vitamin D deficiency in pregnancy is well recognized by the CDC (Center for Disease Control) and ACOG (American College of Obstetrics and Gynecology); however, there is no clear consensus for screening and management due to lack of research data that provides the optimal and safe supplementation.12,13 A pool of evidence relating to the clinical outcomes of vitamin D deficiency in pregnancy is accumulating. Johnson et al.14 reported that in pregnant women, despite living in southern latitudes in the United States, the prevalence of vitamin D disparity was higher in African Americans (97%) compared with Hispanics (81%) and Caucasians (67%). Jackson et al.15 reported that minorities suffer disproportionately (threefold) from perinatal complications due to vitamin D deficiency, which can be associated with a higher risk for pregnancy-related death as compared with whites, and 1
a high prevalence (16%) of pregnancy-induced hypertension (preeclampsia).16–18 The risk of serious complications from preeclampsia is also associated with neonatal morbidity, death, preterm delivery19 and other health conditions10,20,21 that could extend into adulthood.1,2,22–24 In addition, women with no prenatal care had a higher risk of death from preeclampsia or eclampsia than those who had some level of prenatal care.17 Pregnant minorities have been least studied in vitamin D-associated diseases25 despite commonly presenting with any single or combination of high risk comorbidities (that is, obesity, diabetes, hypertension, asthma, limited prenatal care, and low-birthweight infants) associated with poor pregnancy outcomes.3,25,26 This study was designed to investigate the prevalence of vitamin D deficiency in a cohort of pregnant ethnic minorities and analyze association(s) between lower serum 25(OH)D concentration and pregnancy-related comorbidities including neonatal outcomes.
METHODS After approval by the Institutional Review Board at Howard University, this study was conducted from June to September 2012 in Washington, DC to optimize environmental parameters of sunlight exposure. Blood samples were collected from detached umbilical cord immediately following delivery of the infant. Each mother–baby pair was considered one study subject, to include multiple births. Participants were included on the basis of the following criteria: (1) All delivering pregnant female regardless of a history of prenatal care, race or ethnicity, and (2) Provision of written informed consent from the mother. Participants were excluded if: (1) known disorder of parathyroid, calcium or magnesium metabolism, chronic renal disease/failure or uncontrolled thyroid disease, (2) use of
Division of Neonatology, Department of Pediatrics and Child Health, The Howard University College of Medicine and the Howard University Hospital, Washington, DC, USA; Department of Pediatrics and Child Health, Human Genetics, The Howard University College of Medicine and the Howard University Hospital, Washington, DC, USA and 3 Department of Obstetrics and Gynecology, The Howard University College of Medicine and the Howard University Hospital, Washington, DC, USA. Correspondence: Dr IV Reeves, Division of Neonatology, Department of Pediatrics and Child Health, The Howard University College of Medicine and the Howard University Hospital, 2041 Georgia Avenue NW, Washington, DC 20060, USA. E-mail: [email protected] Received 14 November 2013; revised 2 April 2014; accepted 4 April 2014; published online 22 May 2014 2
Vitamin D deficiency, a potential contributor to preeclampsia IV Reeves et al
768 Table 1.
Descriptive characteristics of the study group
Descriptive characteristics Mothers (N = 47) Age (years) Vitamin D level (ng ml − 1) Gravida Parity Time of onset of prenatal care (weeks) Number of prenatal visits Prepregnancy BMI Infants (N = 49) Gestational age (weeks) Birth weight (g) Birth length (cm) Ponderal index (PI) Birth head circumference (cm) Ionized Ca+2 level (mg dl − 1)
Median
Mean
s.e.m.
s.d.
26.00 16.00 3.00 1.00 12.00 7.00 29.60
27.28 17.51 3.55 1.53 16.45 7.60 31.15
1.01 1.15 0.34 0.27 1.28 0.50 1.20
6.95 7.90 2.31 1.84 8.78 3.43 8.21
38.60 2975.00 48.00 2.59 33.50 5.90
37.94 2947.43 47.78 2.67 33.33 5.87
0.35 97.57 0.44 0.05 0.26 0.06
2.42 683.00 3.06 0.32 1.85 0.43
Range 17.00–40.00 5.00–43.00 1.00–10.00 0.00–7.00 5.50–38.40 0.00–18.00 18.90–59.60 31.00–41.00 1735.00–4710.00 42.00–54.00 2.18–3.39 29.00–37.00 4.80–7.20
Abbreviation: BMI, body mass index. Vitamin D levels (conversion: nmol l − 1 divided by 2.5 = ng ml − 1).
anticonvulsants or rifampicin, (3) congenital or family history of bone disorder, and (4) newborn with congenital anomaly. In total, forty-eight mothers were recruited and fifty infant samples were collected; this population included two sets of twins. One mother–baby pair was eliminated on the basis of diagnosed Down’s syndrome following delivery. Prepregnancy body mass index (BMI) was obtained from self-reports or from the prenatal record.
Sample processing Umbilical cord blood was collected in a serum-separator tube (gold top), specimen was de-identified by the study coordinator, coded and sent for determination of serum 25(OH)D and ionized calcium. Laboratory personnel were blinded to all patient identification and medical data. For measurement of 25(OH)D concentration, 3 ml of cord blood sample was immediately processed at Howard University Hospital Clinical Laboratory and transported for analysis to the Nichols Institute Diagnostics, Chantilly, VA, USA. This analysis was by liquid chromatography, tandem mass spectrometry method that employed extraction via protein precipitation with 100% specificity (gold standard) with measuring range of 4 to 100 ng ml − 1 (10 to 260 nM). Ionized calcium concentration was similarly transported and measured using an ion specific electrode method within 24 h of collection of 4 ml of cord blood. This analysis is empirically based on a measured pH and ionized calcium concentration normalized to a pH 7.40.
Statistical analyses Means, medians and standard deviations were calculated for anthropomorphic and physiologic characteristics. Participants were classified as IOM threshold (⩾25 ng ml − 1) or low ( o25 ng ml − 1) based on vitamin D blood concentrations as defined by the IOM 50th percentile for pregnant and lactating women. The t-tests were performed to determine if vitamin D blood levels altered anthropomorphic and physiologic characteristics in mothers and their infants. Bivariate (Fisher’s exact test) and multivariate (Multi-nominal Logistic Regression Analysis) were performed to determine the association between the comorbidities and vitamin D levels (IOM threshold or low) and potentiating factors for preeclampsia. The odds ratios and 95% confidence intervals were calculated for comorbidities and risk factors for preeclampsia. All statistical analyses were performed using SPSS version 20 (SPSS, Chicago, IL, USA).
RESULTS The clinical utility and accuracy of cord blood sampling is justified on the basis of previous studies demonstrating that maternal serum and cord blood levels of 25(OH)D are closely correlated (r = 0.95, P o 0.0001).26–30 Serum concentration of 25(OH)D is an established biomarker of vitamin D status.27,30,31 Journal of Perinatology (2014), 767 – 773
Mother and infant characteristics are described in Table 1. Our study population had a median cord vitamin D concentration of 16 ng ml − 1, which is substantially below the 25th percentile by IOM.28 Notably, our gestational ages were in the third trimester and the median prepregnancy BMI of 29.6 indicated an overweight group (18.9 to 59.6; obese ⩾ 30 by CDC definition). In Table 2, 85.1% (40/47) of our cohort were significantly below the IOM threshold (P = 0.001). Women who entered prenatal care in the first trimester had vitamin D concentrations closer to threshold. Ionized calcium concentrations were unchanged regardless of vitamin D levels. Demographically, our cohort consisted of 80.9% African American, 17% Hispanics and 2.1% Caucasian (Table 3). Intergroup differences between ethnicities approached statistical significance (P = 0.062) for low vitamin D. The incidence of low vitamin D was seen in 89.47% (34/38) of African Americans. Our cohort showed 80.9% women were o 35 years of age, of which 89.47% (34/38) were below the IOM threshold (P = 0.087). The BMI of 48.9% women was ⩾ 30; 95.65% (22/23) of which were below the IOM threshold (P = 0.055). A threefold increase in pregestational diabetes at low vitamin D levels was observed. All cases with chronic hypertension (10.6%) had low vitamin D levels. Table 4 describes the association of selected comorbidities with the risk of developing preeclampsia. There were no direct associations between low 25(OH)D levels and risk for preeclampsia. Gestational diabetes alone was associated with a twofold risk for preeclampsia. Two statistically significant associations were observed: (1) gestational hypertension increased the risk for preeclampsia by 12-fold (OR = 12.375; CI = 2.4 to 63.558, P = 0.003) and (2) the combination of chronic and gestational hypertension increased the risk for preeclampsia by 14-fold (OR = 14.5; CI = 2.555 to 82.278, P = 0.001; Figure 1). DISCUSSION A disproportionate cohort of women with low vitamin D was observed, where 85.1% were below the IOM threshold in pregnancy. This cohort remained deficient despite the study occurring during the months of maximum sunlight exposure and the utilization of prenatal vitamin supplements (78.7% deficient (37/47, not shown in charts)). In a study conducted by Bodnar et al.,32 prenatal Vitamin D supplementation at 400 IU/day in 90% of mothers also did not prevent deficiency. Below the IOM threshold, maternal age (o 35 years), prepregnancy BMI ⩾ 30 © 2014 Nature America, Inc.
Vitamin D deficiency, a potential contributor to preeclampsia IV Reeves et al
7.46 2.63 2.01 9.72 9.59 2.32 797.82 3.35 0.31 2.13 0.33 28.35 2.52 1.43 30.58 17.98 38.10 3052.04 48.21 2.67 33.35 5.96 6.40 2.02 1.66 6.63 7.85 2.59 549.13 2.74 0.34 1.56 0.50 0.685 0.343 0.949 0.978 0.001 0.922 0.145 0.118 0.647 0.144 0.730 − 1.498 − 0.550 0.159 2.175 2.104 1.604 0.108 0.151 0.407 1.068 0.019 0.167 0.919 0.005 0.001 12.161 0.010 2.195 2.535 0.212 2.203 0.121 30.86 4.00 1.43 25.16 10.23 36.69 2921.43 47.61 2.62 32.64 5.87
7.86 1.83 1.81 9.17 1.72 2.81 1004.94 4.18 0.34 2.66 0.47
Low vitamin D and diabetic conditions of pregnancy Vitamin D receptors are present on pancreatic β cells and 1,25 (OH)2D3 is essential for normal insulin release.34 Additional studies have demonstrated prevalence of vitamin D deficiency in type 1 diabetes; and vitamin D supplementation during pregnancy or infancy improves glycemic control.35 Low threshold of vitamin D deficiency increases risk factors for insulin resistance and glucose intolerance,36,37 thereby increasing risk of gestational diabetes in pregnancy.38 No statistical significance for pregestational or gestational diabetes was observed; however, there was a threefold increased risk in the pregestational diabetic cohort below the IOM threshold. This remains an active area of research as critical vitamin D deficiency could be a modifiable risk factor for glucose control during pregnancy.
6.69 2.40 1.87 7.69 9.08 2.32 631.04 2.89 0.32 1.69 0.42
© 2014 Nature America, Inc.
Abbreviation: BMI, body mass index.
Age (years) Gravida Parity Prepregnancy BMI Time of onset of prenatal care (weeks) Gestational age at birth (weeks) Birth weight (g) Birth length (cm) Ponderal index (PI) Birth head circumference (cm) Ionized Ca+2 level (mg dl − 1)
40 40 40 40 40 40 42 42 42 42 37
26.65 3.47 1.55 32.20 17.53 38.26 2951.76 47.80 2.67 33.45 5.87
7 7 7 7 7 7 7 7 7 7 6
s.d. Mean n s.d. Mean n
Vitamin D o25
Low vitamin D and prepregnancy BMI Scholl et al.33 showed, in a large Camden population study involving 2251 pregnancies, that total vitamin D intake correlated inversely with BMI. Bodnar et al.26 established the relationship of prepregnancy BMI to vitamin D deficiency, reporting that there was a higher prevalence of overweight and obese pregnant women among non-Hispanic black women compared with white women (P o 0.01). After confounder adjustment, a 10 kg m −2 increase in maternal BMI was associated with lower concentrations of serum 25(OH)D.32 Similarly, this study showed that lower 25(OH)D levels below IOM threshold were associated with obesity.
24 24 24 24 24 24 25 25 25 25 22
26.25 3.58 1.63 31.69 14.97 37.96 2847.00 47.36 2.66 33.31 5.79
23 23 23 23 23 23 24 24 24 24 21
s.d. Mean s.d. Mean n
Vitamin D o16 P-value t F Vitamin D ⩾ 25
IOM standards Comparisons of anthropomorphic and physiologic characteristics
Table 2.
Comparisons of anthropomorphic and physiologic characteristics with vitamin D level at IOM standards and study group median
n
Vitamin D ⩾ 16
Study group
F
1.604 2.238 0.566 1.150 2.529 1.655 1.123 0.416 0.207 1.744 1.819
t
− 1.036 0.090 0.351 0.459 − 1.180 − 0.191 − 1.052 − 0.976 − 0.086 − 0.083 − 1.327
0.212 0.142 0.456 0.289 0.119 0.205 0.295 0.522 0.651 0.193 0.185
P-value
769 (obesity), pregestational diabetes and chronic hypertension were comorbidities. The median vitamin D levels (16 ng ml − 1) were below the 25th percentile of IOM. It was hypothesized that in the minority population, the comorbidities at IOM threshold might not be apparent. In an attempt to address this concern, these data were further analyzed at the median vitamin D level (16 ng ml − 1) of the minority women in the study. At maternal ages less than 35 years, lower concentrations of 25(OH)D had a two times greater occurrence than minority women above the age of 35 years (Table 3). Also, the risk for pregestational diabetes almost doubled (OR = 3.450) and the risk for chronic hypertension increased by approximately fourfold (OR = 4.842). Gestational hypertension was more prevalent in minority women with low vitamin D levels below IOM (P = 0.042). These data suggested an underestimation of comorbidities at vitamin D below the IOM threshold (Figure 2). These investigations identified, not only high-risk pregnancy comorbidities at levels of vitamin D below the IOM threshold but also their possible association to potentiate preeclampsia. A comparative review of our study with that of other authors is as follows:
Low vitamin D and hypertensive conditions of pregnancy We used current definitions of gestational hypertension, chronic hypertension and preeclampsia.39 A recent study has shown that preeclampsia is seen at lower vitamin D levels.40 Vitamin D has important immunomodulating properties that may help to establish a proper maternal immune response to the placenta.2,32,41 It also regulates key target genes associated with proper implantation of the placenta that may influence fetal–placental development and function.42 Evidence linking lower levels of vitamin D in pregnancy to preeclampsia was reported in a Pittsburgh study that observed an inverse monotonic dose response relationship between 25(OH)D concentration in early pregnancy and preeclampsia: for every 20 ng ml − 1 decline in 25(OH)D levels, the risk of preeclampsia more than doubled.44 Similarly, a nested case control study from North Carolina reported that women with 25 (OH)D levels less than 20 ng ml − 1 had more than five times greater risk of severe preeclampsia than those with levels of Journal of Perinatology (2014), 767 – 773
770
Comorbid risk factors and their association with vitamin D thresholds (IOM 50th percentile>25 ng/ml and Study Group median> 16 ng/ml) during pregnancy
Comorbid factors associated by Vitamin D
A
B
Frequency of total
Vitamin D o25
Vitamin D o16
Vitamin D o25
Vitamin D ⩾ 25
Fisher’s exact
n (%)
Anova P-value
Anova P-value
n (%)
n (%)
P-value
26 (55.3) 14 (29.8)
5 (10.6) 2 (4.3)
0.553
C Odds ratio
95% Confidence interval
Vitamin D o16
Vitamin D ⩾ 16
Fisher’s exact
Lower
Upper
n (%)
n (%)
P-value
0.743
0.127
4.334
14 (29.8) 10 (21.3)
17 (36.2) 6 (12.8)
0.207
0.429
0.833
0.728
0.954
23 (48.9) 1 (2.1)
19 (40.4) 4 (8.5)
5 (10.6) 2 (4.3)
0.467
1.600
0.261
9.812
16 (34) 8 (17)
32 (68.1) 8 (17)
5 (10.6) 2 (4.3)
0.467
1.600
0.261
9.812
0.286
37 (78.7) 3 (6.4)
6 (12.8) 1 (2.1)
0.488
2.056
0.182
0.899
0.957
35 (74.5) 5 (10.6)
6 (12.8) 1 (2.1)
0.643
1.167
38 (80.9) 9 (19.1)
0.048
0.885
32 (68.1) 8 (17)
6 (12.8) 1 (2.1)
0.596
Obesity BMIo30 BMI ⩾30
24 (51.1) 23 (48.9)
0.730
0.667
18 (38.3) 22 (46.8)
6 (12.8) 1 (2.1)
Newborn gender Male Female
26 (55.3) 21 (44.7)
0.483
0.322
23 (48.9) 17 (36.2)
Mode of delivery Vaginal C-section
17 (36.2) 30 (63.8)
0.659
0.434
Gestational age o37 weeks ⩾ 37 weeks
11 (23.4) 36 (76.6)
0.196
Maternal age o35 years ⩾ 35 years
38 (80.9) 9 (19.1)
0.087
© 2014 Nature America, Inc.
Upper
0.494
0.144
1.699
0.160
4.842
0.498
47.056
21 (44.7) 2 (4.3)
0.042
0.190
0.035
1.022
20 (42.6) 4 (8.5)
17 (36.2) 6 (12.8)
0.333
1.765
0.426
7.307
23.162
23 (48.9) 1 (2.1)
20 (42.6) 2 (6.4)
0.280
3.450
0.332
35.857
0.115
11.814
21 (44.7) 3 (6.4)
20 (42.6) 3 (6.4)
0.646
1.050
0.189
5.826
0.667
0.070
6.353
20 (42.6) 4 (8.5)
18 (38.3) 5 (10.6)
0.471
1.389
0.322
5.986
0.055
0.136
0.015
1.239
12 (25.5) 12 (25.5)
12 (25.5) 11 (23.4)
0.557
0.917
0.292
2.879
3 (6.4) 4 (8.5)
0.377
1.804
0.356
9.142
15 (31.9) 9 (19.1)
11 (23.4) 12 (25.5)
0.237
1.818
0.568
5.817
15 (31.9) 25 (53.2)
2 (4.3) 5 (10.6)
0.501
1.500
0.258
8.722
10 (21.3) 14 (29.8)
7 (14.9) 16 (34)
0.310
1.633
0.490
5.437
0.351
8 (17) 32 (68.1)
3 (6.4) 4 (8.5)
0.197
0.333
0.062
1.798
7 (14.9) 17 (36.2)
4 (8.5) 19 (40.4)
0.272
1.956
0.486
7.867
0.246
34 (72.3) 6 (12.8)
4 (8.5) 3 (6.4)
0.117
4.250
0.753
23.981
21 (44.7) 3 (6.4)
17 (36.2) 6 (12.8)
0.209
2.471
0.537
11.368
0.632
5 (10.2) 26 (53.1) 11 (22.4)
1 (2.0) 3 (6.1) 3 (6.1)
4 (8.2) 15 (30.6) 6 (12.2)
2 (4.1) 14 (28.6) 8 (16.3)
0.311
34 (72.3) 1 (2.1) 5 (10.6)
4 (8.5) 0 3 (6.4)
21 (44.7) 0 3 (6.4)
17 (36.2) 1 (2.1) 5 (10.6)
0.747
Chronic hypertension (−) (+)
42 (89.4) 5 (10.6)
0.333
0.148
35 (74.5) 5 (10.6)
7 (14.9) 0
Gestational hypertension (−) (+)
37 (78.7) 10 (21.3)
0.618
0.040
32 (68.1) 8 (17)
Pregestational or gestational diabetes (−) 37 (78.7) (+) 10 (21.3)
0.618
0.441
Pregestational diabetes (−) (+)
43 (91.5) 4 (8.5)
0.563
Gestational diabetes (−) (+)
41 (87.2) 6 (12.8)
Asthma (−) (+)
Ethnicity African American Caucasian Hispanic
38 (80.9) 1 (2.1) 8 (17)
0.062
95% Confidence interval Lower
Chronic and gestational hypertension (− ) 31 (66) (+) 16 (34)
Birth weight (percentile adjusted for gestational age) Low (⩽25th) 6 (12.2) 0.629 Middle (>25 to o75th) 29 (59.2) High (⩾75th) 14 (28.6)
Odds ratio
(A) Frequency in study, ANOVA for Vitamin D of o25 ng/ml and o16 ng/ml, respectively. (B) Vitamin D levels cut off of 25 ng/ml and (C) Vitamin D levels cut off of 16 ng/ml. Statistical analysis using Fishers Exact test and Logistic regression for risk.
Vitamin D deficiency, a potential contributor to preeclampsia IV Reeves et al
Journal of Perinatology (2014), 767 – 773
Table 3.
Vitamin D deficiency, a potential contributor to preeclampsia IV Reeves et al
771 Table 4.
Comorbid factors as risk for preeclampsia
Comorbid factors contributing to preeclampsia
Preclampsia
Fisher's exact
Negative n (%)
Positive n (%)
P-value
Chronic and gestational hypertension (− ) (+)
29 (61.7) 8 (17)
2 (4.3) 8 (17)
0.001
Chronic hypertension (−) (+)
38 (72.3) 3 (6.4)
8 (17) 2 (4.3)
Gestational hypertension (−) (+)
33 (70.2) 4 (8.5)
Pregestational diabetes (−) (+)
Odd's ratio
95% Confidence interval Lower
Upper
14.500
2.555
82.278
0.285
2.833
0.404
19.873
4 (8.5) 6 (12.8)
0.003
12.375
2.409
63.558
34 (72.3) 3 (6.4)
9 (19.1) 1 (2.1)
0.630
1.259
0.117
13.599
Gestational diabetes (−) (+)
33 (70.2) 4 (8.5)
8 (17) 2 (4.3)
0.378
2.063
0.320
13.313
Asthma (−) (+)
29 (61.7) 8 (17)
9 (19.1) 1 (2.1)
0.375
0.403
0.044
3.669
Obesity BMI o30 BMI ⩾30
20 (42.6) 17 (36.2)
4 (8.5) 6 (12.8)
0.333
1.765
0.426
7.307
Gestational age o37 weeks ⩾ 37 weeks
7 (14.9) 30 (63.8)
4 (8.5) 6 (12.8)
0.164
0.350
0.077
1.583
Maternal age o35 years ⩾ 35 years
29 (61.7) 8 (17)
9 (19.1) 1 (2.1)
0.375
0.403
0.044
3.669
Vitamin D level of 25 (ng ml − 1) Vitamin D o25 Vitamin D ⩾ 25
31 (66) 6 (12.8)
9 (19.1) 1 (2.1)
0.533
0.574
0.061
5.410
Vitamin D level of 16 (ng ml − 1) Vitamin D o16 Vitamin D ⩾16
17 (36.2) 20 (42.6)
7 (14.9) 3 (6.4)
0.160
0.364
0.081
1.631
Statistics of Fisher's exact test and logistic regression for risk.
at least 30 ng ml − 1.45 Also, a large epidemiological study from Norway in nulliparous pregnant women showed a 27% reduction in risk of preeclampsia (OR = 0.73; CI = 0.58 to 0.92) with vitamin D supplementation of 10 to 15 μg dl − 1 as compared with no supplementation. All together, these findings support the hypothesis that maternal vitamin D deficiency may be an independent risk factor for preeclampsia.11 With regard to the timing of deficiency, a study in 274 nulliparous pregnant women showed that vitamin D deficiency at or before week 22 of gestation was an independent predictor of preeclampsia and low vitamin D status in the neonate. Patients with 25(OH)D levels at 15 ng ml − 1 had a fivefold increase in the risk of preeclampsia, despite receiving prenatal vitamins.44 Previous studies have shown that the incidence and severity of preeclampsia are multifactorial in associations with chronic hypertension46 and pregestational diabetes mellitus.46,47 This study revealed that both types of hypertension (chronic and/or © 2014 Nature America, Inc.
gestational) potentiated an increased risk for preeclampsia. In addition, Evensen et al.48 showed increased odds for preeclampsia with gestational diabetes. Vitamin D deficiency in the mode of delivery, gestational outcomes, growth parameters and serum ionized calcium. An observational study from Australia has shown no association between maternal 25(OH)D status with the mode of delivery and gestational ages; however, there was an association with low birth weight.49 Although African Americans are more likely to deliver low-birthweight infants,50 this was not seen in our infant cohort. The median growth parameters (weight, length, head circumference and PI) for gestational age were within the 50th percentile. When infant weights were adjusted for corresponding gestational age, there were no birth weight differences associated with lower vitamin D concentration. Although not statistically significant, Journal of Perinatology (2014), 767 – 773
Vitamin D deficiency, a potential contributor to preeclampsia IV Reeves et al
772 Association of Comorbidities with Preeclampsia
16.00
p=0.001
14.00 p=0.003
Odd's Ratio
12.00 10.00 8.00
CONCLUSION In these investigations, a cohort of ethnic minority pregnant women had vitamin D concentrations below the IOM median level, which appeared to contribute a substantial risk for preeclampsia. Vitamin D deficiency can be treated and, if therapeutic intervention occurs in early stages of gestation, could result in healthy pregnancy outcomes.
6.00
CONFLICT OF INTEREST
4.00
The authors declare no conflict of interest. 2.00
Vitamin D level of 16 (ng/mL)
Vitamin D level of 25 (ng/mL)
Maternal Age
Gestational age
Obseity
Asthma
Gestational Diabetes
Pregestational Diabetes
Gestational Hypertension
Chronic Hypertension
Chronic and Gestational Hypertension
0.00
Comorbidities contributing to Preeclampsia
Figure 1. Comparing odd ratios of preeclampsia to pregnancy comorbidities.
5.000 Vitamin D
