Objective
Recently, vitamin D deficiency has been associated with increased risks for preeclampsia and diagnosis of early-onset, severe preeclampsia (EOSPE). The purpose of this investigation was to examine the association between vitamin D levels and small-for-gestational age (SGA) in patients with EOSPE.
Study Design
Patients with EOSPE were recruited, and demographics, outcomes, and plasma were collected. We assessed 25-hydroxyvitamin D (25[OH]D) by radioimmunoassay and reported our findings in nanograms per milliliter. Results were analyzed by Mann-Whitney U test and Spearman correlation and were reported as median (Q1-Q3).
Results
In patients with EOSPE (n = 56), 25(OH)D was lower in patients with SGA (16.8 ng/mL; range, 8.9–23 ng/mL) vs normal fetal growth (25.3 ng/mL; range, 16–33 ng/mL; P = .02). 25(OH)D was correlated significantly with percentile growth at delivery (ρ = 0.31; P = .02).
Conclusion
Vitamin D is lower among patients with SGA in EOSPE than those without growth retardation. We suspect that vitamin D may impact fetal growth through placental mechanisms.
Vitamin D is a secosterol hormone that is recognized primarily for its role in calcium homeostasis. 25-hydroxyvitamin D (25[OH]D) is an important measure of physiologic vitamin D status and has a half-life of approximately 2 weeks. The active form of vitamin D, 1,25-(OH) 2 D 3 is produced through hydroxylation of 25(OH)D in the kidney or placenta and has a very short half-life that is measured in minutes. Thus, most studies have focused on the assessment of vitamin D influence on disease with the use of 25(OH)D levels. However, recent evidence suggests that vitamin D, and especially a deficiency of vitamin D, which is common in the United States, may be involved in adverse pregnancy outcomes. We recently reported an association between low maternal 25(OH)D and early-onset, severe preeclampsia (EOSPE). Women with a diagnosis of EOSPE had significantly lower 25(OH)D levels, and the data suggested a potential reduction of the risk of preeclampsia with only a 10-ng/mL increase in maternal 25(OH)D. Bodnar et al found that vitamin D deficiency in the second trimester that was measured by 25(OH)D was also associated with an increased risk for preeclampsia. Epidemiologic evidence has also linked insufficient vitamin D intake and preeclampsia risk among nulliparous pregnancies.
EOSPE contributes to 15% of the preterm births in the United States per annum and likely contributes to increased risk for vascular disease in later life. These women and their fetuses are also recognized to be at great risk for adverse pregnancy outcome with a 20-fold increased risk for maternal death and several-fold higher risk for neonatal morbidity or death, which is dependent on gestational age at delivery and presence of growth restriction in the fetus. Thus, this group may serve as a target population for the improvement of outcomes that are associated with preeclampsia.
The purpose of this investigation was to examine the maternal plasma level of 25(OH)D in cases of EOSPE that resulted in the delivery of a small-for-gestational-age (SGA) infant, relative to pregnancies with EOSPE and normal fetal growth.
Materials and Methods
The institutional review board at the Medical University of South Carolina approved this nested case-control investigation from a prospective study of patients with EOSPE who were enrolled at Medical University of South Carolina from 2007-2010. Patients who were included in this investigation consented to the collection of demographic and outcome data and venipuncture for the collection of plasma to be used for 25(OH)D analysis. Subjects were recruited from the inpatient Labor and Delivery unit at Medical University of South Carolina after confirmation of a diagnosis of EOSPE. EOSPE was defined as meeting the American College of Obstetrics and Gynecology criteria for severe preeclampsia and having this diagnosis at <34 weeks’ completed gestational age. Patients with EOSPE or healthy control subjects were excluded if they also had a diagnosis of chronic hypertension, pregestational diabetes mellitus, renal disease, lupus, or tobacco use. Demographic data that were collected on each EOSPE case at the time of plasma collection included gestational age, maternal age, maternal prepregnancy body mass index, maternal systolic and diastolic blood pressure, and urine protein. Plasma was collected in a vacutainer tube (BD P100, version 1.1, EDTA; Becton Dickinson, Franklin Lakes, NJ), which contained a protease inhibitor cocktail from EOSPE cases at the time of diagnosis. Samples were processed and frozen in aliquots within 30 minutes of collection from each subject. The antepartum plasma sample that had been collected at the time of diagnosis of EOSPE was assessed for total 25(OH)D in nanograms per milliliter with the use of double antibody radioimmunoassay (DiaSorin, Stillwater, MN). In our laboratory, this assay has a <10% interassay and intraassay reliability. After delivery, outcome data were collected on EOSPE cases that included birthweight, gestational age at delivery, and an assessment of birthweight percentile with SGA that was defined as birthweight <10th percentile as assessed by gestational age at delivery. Cases were defined as patients with EOSPE and an SGA fetus vs control subjects who were patients with EOSPE and normal fetal growth.
Results of continuous and categoric variables were reported as median (25th-75th percentile) and percentage by case or control group, respectively. Bivariable analysis was conducted with the Mann Whitney U test for examination of continuous variables (maternal age, prepregnancy body mass index, gestational age at plasma sample collection, gestational age at delivery, mean arterial pressure at sample collection, birthweight, and plasma 25(OH)D levels) by case or control group. Proportions were compared by case or control group with the χ 2 test. The distribution of data points was assessed by Shapiro-Wilk W test. Correlation between maternal 25(OH)D at diagnosis of EOSPE and percentile growth was determined by Spearman rank correlation (ρ). Simple linear regression was conducted between percentile growth and maternal 25(OH)D for examination of the slope of regression line. F test and r 2 values were calculated to assess the fit of the regression model. All statistical tests were 2-sided with alpha set at 0.05 to control for type I error. Data analysis was performed with SAS software (version 9.2; SAS Institute Inc, Cary, NC).
Results
Fifty-six patients with EOSPE were consented and included in this investigation ( Figure 1 ). Pregnancy demographics and outcomes are summarized by patients with EOSPE with SGA (cases) or patients with EOSPE with normal growth (controls) in the Table . The data for patients with an SGA fetus were noted to be similar to those patients with normal growth at delivery with respect to all demographics, except for the gestational age at delivery and plasma 25(OH)D levels. The median plasma 25(OH)D level among patients with SGA was 33% less than those patients who exhibited normal growth at delivery (SGA 16.8 ng/mL vs normal 25.3 ng/mL; P = .02). Because patients with an SGA fetus were delivered at a higher gestational age, we converted all birthweights to percentile growth for gestational age as a means of controlling for different gestational ages at delivery. A positive correlation was demonstrated (ρ = 0.31; P = .02) between percentile growth and maternal 25(OH)D levels. To examine the relationship between percentile growth and maternal 25(OH)D levels, a simple linear regression was performed. The simple linear regression model determined the slope of the fitted regression line as y = 17.5 + 0.22x, where x is the percentile birthweight and y is the maternal 25(OH)D level. The model, as shown in Figure 2 , had excellent goodness of fit as assessed by F test ( P = .004) and an r 2 value of 0.14. ( Figure 2 )
| Variables | Small for gestational age (n = 33) | Normal growth (n = 23) | P value |
|---|---|---|---|
| Age, y a | 24 (21–29) | 24 (21–30) | NS b |
| Nulliparity, % | 25 | 36 | NS c |
| Gestation at delivery, wk a | 31 (29–33) | 29 (27–30) | .01 b |
| African American race, % | 34 | 13 | NS c |
| Mean arterial pressure, mm Hg a | 123 (120–130) | 129 (120–130) | NS b |
| Body mass index, kg/m 2a | 32 (25–37) | 34 (29–38) | NS b |
| 25-hydroxyvitamin D, ng/mL a | 16.8 (8.9–23) | 25.3 (16–33) | .02 b |
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