International Journal of Gynecology and Obstetrics 130 (2015) 54–58
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CLINICAL ARTICLE
Low vitamin D status among pregnant Latin American and Caribbean women with HIV Infection Jennifer Jao a,b,⁎, Laura Freimanis c, Marisa M. Mussi-Pinhata d, Rachel A. Cohen c, Jacqueline P. Monteiro d, Maria L. Cruz e, Rhoda S. Sperling b, Andrea Branch a, George K. Siberry f, for the NISDI LILAC Protocol 1 a
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA Department of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA Westat, Rockville, MD, USA d Faculdade de Medicina, Universidade de São Paulo, Ribeirão Preto, Brazil e Serviço de Doenças Infecciosas e Parasitárias, Hospital Federal dos Servidores do Estado, Rio de Janeiro, Brazil f Eunice Kennedy Shriver National Institute of Child Health and Human Development, Maternal and Pediatric Infectious Disease Branch, Bethesda, MD, USA b c
a r t i c l e
i n f o
Article history: Received 16 October 2014 Received in revised form 8 January 2015 Accepted 26 March 2015 Keywords: Caribbean HIV Latin America Pregnancy Vitamin D
a b s t r a c t Objective: To evaluate the prevalence and predictors of low vitamin D status among pregnant women with HIV infection. Methods: The present cross-sectional study analyzed repository specimens collected at 12–34 weeks of pregnancy among women enrolled across 17 sites in Latin America and the Caribbean between 2002 and 2009. Logistic regression modeling was used to identify factors associated with low vitamin D status (25-hydroxyvitamin D b30 ng/mL). Results: Among 715 women, 218 (30.5%) were vitamin D deficient (b20 ng/mL) and 252 (35.2%) were insufficient (21–29 ng/mL). Factors associated with low vitamin D status included residence in subtropical latitudes (adjusted odds ratio [aOR] 1.97, 95% confidence interval [CI] 1.35–2.88), assessment during non-summer seasons (autumn: aOR 1.85, 95% CI 1.20–2.86; spring: 4.3, 2.65–6.95; winter: 10.82, 5.74–20.41), employment (aOR 1.56, 95% CI 1.06–2.38), and assessment before 20 weeks of pregnancy (aOR 1.89, 95% CI 1.18–3.06). Factors protective against low vitamin D status were CD4 count below 200 cells per mm3 (aOR 0.45, 95% CI 0.26–0.77) and protease inhibitors (aOR 0.62, 95% CI 0.40–0.95). Conclusion: Low vitamin D status was prevalent among pregnant women with HIV infection. Further studies are warranted to identify the impact of low maternal vitamin D status. © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction The role of vitamin D in preventing complications among adults with HIV infection—e.g. osteoporosis, fractures, diabetes, and even opportunistic infections—has been an increasingly active area of scientific research. Recent studies [1–3] have linked low vitamin D levels among adults with HIV infection with disease progression, subclinical cardiovascular disease, and possibly bone loss. In addition, low vitamin D status in pregnancy has been associated with adverse maternal and neonatal outcomes, such as maternal periodontal disease [4], preeclampsia [5], gestational diabetes [6], small-for-gestational-age birth weight [7], poor infant and childhood skeletal development [8], and early childhood respiratory infections [9].
⁎ Corresponding author at: Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1087, New York, NY 10029, USA. Tel.: +1 212 824 7497; fax: +1 212 824 2317. E-mail address: [email protected] (J. Jao). 1 Members of the NISDI Perinatal Study Group are given in Supplementary Material S1.
The biological effects of vitamin D could be especially relevant for pregnant women because vitamin D is essential for healthy bones, and is also an important immune modulator that enhances both innate and adaptive immune responses while reducing inflammation. However, few studies have examined vitamin D status among pregnant women with HIV infection. The aim of the present study was therefore to describe the prevalence of low vitamin D levels and identify factors associated with this status among pregnant Latin American and Caribbean women infected with HIV. 2. Materials and methods The present cross-sectional study analyzed vitamin D status among pregnant women enrolled in the National Institute of Child Health and Human Development (NICHD) International Site Development Initiative (NISDI) cohort between January 1, 2002, and December 31, 2009. Informed consent was obtained from all enrolled participants. The study was approved by the institutional review boards of the NICHD and Westat, and in-country ethics committees and national review boards (where appropriate).
http://dx.doi.org/10.1016/j.ijgo.2015.01.017 0020-7292/© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
J. Jao et al. / International Journal of Gynecology and Obstetrics 130 (2015) 54–58
From 2002 to 2009, the Eunice Kennedy Shriver NICHD (Bethesda, MD, USA) enrolled a prospective cohort of pregnant women with HIV infection and their neonates into the NISDI Perinatal protocol and Longitudinal Study in Latin American Countries (LILAC) protocol in Latin America and the Caribbean. In total, 17 sites across Argentina, the Bahamas, Brazil, Mexico, Peru, and Jamaica participated. Women at more than 8 weeks of pregnancy were eligible for the Perinatal protocol, whereas those at more than 22 weeks were eligible for the LILAC protocol. Study visits were conducted prepartum (≤2 visits), at delivery, and until 6 months (Perinatal protocol) or 2 years (LILAC protocol) postpartum. Information collected during the maternal study visits included medical history, physical examinations, and laboratory assessments (hematology, flow cytometry assays, HIV RNA level, and biochemistry). In addition, peripheral blood mononuclear cells and plasma specimens were collected from mothers and infants, and stored at −80 °C for potential future studies. The present study population was restricted to Latin American and Caribbean pregnant women with HIV infection who were enrolled for the first time (subsequent pregnancies were not included) in the NISDI Perinatal and/or LILAC protocols and for whom prepartum blood specimens collected between 12 and 34 weeks of pregnancy were available. Only women whose pregnancies resulted in singleton live births of a neonate without HIV infection were included. 25(OH)D is the clinical indicator of vitamin D status and the precursor of the most biologically active form of vitamin D, 1,25dihydroxyvitamin D. Maternal plasma 25-hydroxyvitamin D (25(OH)D) levels were measured in the repository sample with an Abbott Architect chemiluminescent microparticle immunoassay [10] on an Architect i2000SR analyzer (Abbott, Abbott Park, IL, USA), according to the manufacturer’s instructions, at ARUP Laboratories (Salt Lake City, UT, USA). The samples, which had been previously processed and stored in aliquots at −80 °C in a central repository, were shipped frozen and maintained below −80 °C until the time that the vitamin D assay was performed. Vitamin D deficiency was defined as a 25(OH)D level of 20 ng/mL or less, insufficiency as 21–29 ng/mL, and sufficiency as 30 ng/mL or more [11]. Low vitamin D status was defined as vitamin D insufficiency or deficiency (b30 ng/mL). Information was collected on maternal sociodemographics, gestational age, season at the time of vitamin D assessment, substance use during pregnancy, immunological status, and the antiretroviral therapy (ART) regimen received (defined as the regimen taken for ≥28 days before the date of vitamin D assessment) during pregnancy. The latitude category of the site at which women were enrolled was assigned as tropical if the site was located between the Tropic of Cancer (23.4378°N) and the Tropic of Capricorn (23.4378°S) or subtropical if between the tropical circle of latitude (the Tropic of Cancer or Tropic of Capricorn) and the 35th parallel in each hemisphere. Statistical analyses were performed via SAS version 9.3 (SAS Institute, Cary, NC, USA). Prevalence estimates, including 95% confidence intervals (CIs), were calculated by the exact binomial method. Associations of categorical variables with low vitamin D status were evaluated via the Fisher exact test. Variables that were at least marginally associated with low vitamin D status (P ≤ 0.10) were considered candidates for multivariable analysis. Logistic regression modeling was used to identify factors independently associated with low vitamin D status in pregnancy. P b 0.05 was taken to be statistically significant. 3. Results After excluding women enrolled after 35 weeks of pregnancy (n = 177), those without prenatal blood specimens (n = 60), and specimens from repeat pregnancy enrollments (n = 47), 715 pregnant women with HIV infection were included in the present analysis. At the prenatal visit, the mean maternal age was 28.6 ± 5.7 years and the mean length of pregnancy was 25 ± 6.3 weeks. Approximately
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one-quarter of participants had a gestational age of less than 20 weeks at the time of the vitamin D assessment (Table 1). Overall, 542 (75.8%) women had completed at least 7 years of education. Tobacco use during pregnancy was reported by more than one-fifth of participants and alcohol use by more than 10% (Table 1). Marijuana was the most frequent illicit substance used during pregnancy (2.5%). At enrollment, 113 (15.9%) women had a CD4 count of 200 cells per mm3 or less, and 318 (44.8%) had an HIV RNA level of 1000 copies per mL or higher. Approximately 10% were classified as HIV class C by the US Centers for Disease Control (CDC) classification. A total of 322 (45.1%) women had received three-drug combination ART (cART), whereas 337 (47.1%) had not received ART for at least 28 days at the time of the vitamin D assessment. All non-nucleoside reverse transcriptase inhibitor (NNRTI)-based cART included nevirapine (n = 127), whereas protease inhibitor (PI)-based cART (n = 195) included lopinavir/ritonavir (n = 123), nelfinavir (n = 63), atazanavir (n = 3), fosamprenavir or amprenavir (n = 3), saquinavir (n = 2), or indinavir (n = 1). Eleven (1.5%) women received tenofovir as part of their cART. The mean plasma vitamin D level at the prepartum visit was 25.5 ± 9.8 ng/mL. Overall, 218 (30.5%; 95% CI 27.13%–33.96%) of pregnant women were vitamin D deficient, and an additional 252 (35.2%; 95% CI 31.74%–38.75%) were insufficient. Only 245 (34.3%; 95% CI 30.79%–37.87%) women were sufficient. The mean 25(OH)D levels were 15.3 ± 3.1 ng/mL, 25.0 ± 2.6 ng/mL, and 36.9 ± 6.5 ng/mL among women who were vitamin D deficient, insufficient, and sufficient, respectively. Overall, 470 (65.7%; 95% CI 62.13%–69.21%) women met the criteria for low vitamin D status. The following variables were included in the final logistic regression model: latitude circle of the site, employment status, gestational age, season of vitamin D assessment, CD4 count at enrollment, and ART regimen. Factors associated with increased risk of low vitamin D status in multivariate analysis included residence in subtropical latitudes, vitamin D assessment during a non-summer season, vitamin D assessment after fewer than 20 weeks of pregnancy, and gainful employment (Table 2). Factors associated with decreased risk of low vitamin D status included a CD4 count below 200 cells per mm3 or between 200 and 499 cells per mm3, and receipt of a PI-based cART regimen (Table 2). 4. Discussion There was a high prevalence of vitamin D insufficiency and deficiency among the present cohort of Latin American and Caribbean pregnant women with HIV infection, despite their residence in tropical and subtropical latitudes. Women who lived in subtropical latitudes, were gainfully employed, were at an early stage of pregnancy, and were assessed outside of summer were at increased risk of deficiency, whereas those receiving PI-based cART and with a lower initial CD4 cell count were at decreased risk. The high rates of low vitamin D status observed in the present study are consistent with the few data that have been published so far for pregnant women with HIV infection. For example, in a large Tanzanian study of 884 pregnant women with HIV infection [12], 39% had low vitamin D status (b80 nmol/L or b30 ng/mL), whereas a smaller nested case–control study in India found rates close to 98% [13]. The mean 25(OH)D levels in the present cohort (25.5 ng/mL) were slightly lower but similar to those in the Tanzanian study (35.7 ng/mL), and slightly higher but similar to those in the smaller Indian case–control study (15.25 ng/mL). Low levels of vitamin D are common in pregnancy worldwide. Although definitions of low vitamin D status vary among studies, rates of hypovitaminosis D reported during pregnancy range from 20% to 98% in countries such as The Gambia [14], Brazil [15], Turkey [16], Iran [17], China [18], and South India [19]. One study of 84 pregnant Brazilian adolescents reported that 43% of participants had a 25(OH)D level of less than 50 nmol/L (25 ng/mL) [15], whereas another reported that 86% of pregnant women with gestational diabetes had a 25(OH)D
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J. Jao et al. / International Journal of Gynecology and Obstetrics 130 (2015) 54–58
Table 1 Characteristics of participants by vitamin D levels.a Characteristics
Maternal age at enrollment, y b20 20–29 N29 Length of pregnancy at vitamin D assessment, wk b20 ≥20 Ethnic origin Black Other White Maternal education, y 0–6 7–12 ≥13 Number in household 1–3 ≥4 Gainful employment Tobacco use in pregnancy Alcohol use in pregnancy Crack/cocaine use in pregnancy Marijuana use during pregnancy Reason for ART Prophylaxis Treatment Missing data CD4 count at enrollment, cells per mm3 b50 50–200 201–350 351–500 N500 Missing data CD4% at enrollment b14 14–28 ≥29 Missing data HIV RNA level at enrollment, copies per mL b1000 1000–10 000 ≥10 000 Missing CDC clinical classification at enrollment A B C ART regimen at time of sample (≥28 d) No ART ≥28 d 2 NRTIs and 1 NNRTI 2 NRTIs and 1 PI Dual Mono Other Season when prepartum blood sample obtained Summer Autumn Spring Winter Latitude circle Tropical Subtropical
Vitamin D levels
Odds ratio (95% CI)
P value d
Low b (n = 470)
Sufficient c (n = 245)
Total (n = 715)
20 (4.3) 235 (50.0) 215 (45.7) 24.8 ± 6.5 107 (22.8) 363 (77.2)
17 (6.9) 131 (53.5) 97 (39.6) 25.9 ± 6.0 35 (14.3) 210 (85.7)
37 (5.2) 366 (51.2) 312 (43.6)
0.66 (0.33–1.30) Ref. 1.24 (0.90–1.70)
142 (19.9) 573 (80.1)
1.77 (1.16–2.68) Ref.
81 (17.2) 199 (42.3) 190 (40.4)
53 (21.6) 105 (42.9) 87 (35.5)
134 (18.7) 304 (42.5) 277 (38.7)
0.70 (0.46–1.07) 0.87 (0.61–1.23) Ref.
0.2603
100 (21.3) 339 (72.1) 31 (6.6)
73 (29.8) 160 (65.3) 12 (4.9)
173 (24.2) 499 (69.8) 43 (6.0)
0.53 (0.26–1.10) 0.82 (0.41–1.64) Ref.
0.0383
228 (48.5) 242 (51.5) 135 (28.7) 106 (22.6) 49 (10.4) 19 (4.0) 10 (2.1)
112 (45.7) 133 (54.3) 54 (22.0) 53 (21.6) 32 (13.1) 7 (2.9) 8 (3.3)
340 (47.6) 375 (52.4) 189 (26.4) 159 (22.2) 81 (11.3) 26 (3.6) 18 (2.5)
Ref. 0.89 (0.66–1.22) 0.70 (0.49–1.01) 1.05 (0.73–1.53) 0.77 (0.48–1.25) 1.43 (0.59–3.46) 0.64 (0.25–1.65)
0.5280
196 (42.2) 269 (57.8) 5
82 (34.0) 159 (66.0) 4
278 (39.4) 428 (60.6) 9
Ref. 0.71 (0.51–0.98) –
0.0422
4 (0.9) 63 (13.4) 124 (26.4) 119 (25.4) 159 (33.9) 1
5 (2.0) 41 (16.8) 82 (33.6) 53 (21.7) 63 (25.8) 1
9 (1.3) 104 (14.6) 206 (28.9) 172 (24.1) 222 (31.1) 2
0.32 (0.08–1.22) 0.61 (0.37–0.99) 0.60 (0.40–0.90) 0.89 (0.58–1.38) Ref. –
0.0341
40 (9.9) 191 (47.4) 172 (42.7) 67
19 (9.4) 107 (53.0) 76 (37.6) 43
59 (9.8) 298 (49.3) 248 (41.0) 110
0.93 (0.51–1.71) 0.79 (0.55–1.13) Ref. –
0.4285
258 (55.1) 94 (20.1) 116 (24.8) 2
135 (55.6) 55 (22.6) 53 (21.8) 2
393 (55.3) 149 (21.0) 169 (23.8) 4
Ref. 0.89 (0.60–1.32) 1.15 (0.78–1.68) –
0.5805
407 (86.6) 23 (4.9) 40 (8.5)
195 (79.6) 20 (8.2) 30 (12.2)
602 (84.2) 43 (6.0) 70 (9.8)
Ref. 0.55 (0.30–1.03) 0.64 (0.39–1.06)
0.0456
241 (51.3) 86 (18.3) 107 (22.8) 12 (2.6) 14 (3.0) 10 (2.1)
96 (39.2) 41 (16.7) 88 (35.9) 4 (1.6) 11 (4.5) 5 (2.0)
337 (47.1) 127 (17.8) 195 (27.3) 16 (2.2) 25 (3.5) 15 (2.1)
Ref. 0.84 (0.54–1.30) 0.48 (0.34–0.70) 1.19 (0.38–3.80) 0.51 (0.22–1.16) 0.80 (0.27–2.39)
b0.001
78 (16.6) 127 (27.0) 145 (30.9) 120 (25.5)
88 (35.9) 96 (39.2) 45 (18.4) 16 (6.5)
166 (23.2) 223 (31.2) 190 (26.6) 136 (19.0)
Ref. 1.49 (1.00–2.24) 3.64 (2.31–5.72) 8.46 (4.62–15.48)
b0.001
169 (36.0) 301 (64.0)
129 (52.7) 116 (47.3)
298 (41.7) 417 (58.3)
Ref. 1.98 (1.45–2.71)
b0.001
0.1350
0.0388 b0.001
0.0606 0.8498 0.3203 0.5298 0.4508
Abbreviations: CI, confidence interval; ART, antiretroviral therapy; CDC, Centers for Disease Control; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. a Values are given as number (percentage) or mean ± SD, unless indicated otherwise. b b30 ng/mL. c ≥30 ng/mL. d By t test for continuous variables and χ2 test for categorical variables.
level of less than 30 ng/mL [20]. An even smaller study in Argentina reported that 62% of women had 25(OH)D levels of less than 8 ng/mL at delivery [21]. High-income countries have reported similar rates. In
the USA, for example, the proportion of women with low vitamin D was found to range from 50% to 85% [22], with African Americans and Hispanics at highest risk. Reported rates of low vitamin D in other
J. Jao et al. / International Journal of Gynecology and Obstetrics 130 (2015) 54–58 Table 2 Factors associated with low vitamin D status in pregnancy in logistic regression. Factor
ART lasting ≥28 d at or around vitamin D assessment No ART ≥28 d 2 NRTIs and 1 NNRTI 2 NRTIs and 1 PI Dual Mono Other CD4 cell count at enrollment, cells per mm3 ≥500 200–499 b200 Gainful employment Yes No Season of vitamin D assessment Summer Autumn Spring Winter Latitude circle of site location Tropical Subtropical Length of pregnancy at time of vitamin D assessment, wk ≥20 b20
Adjusted odds ratio (95% Wald confidence limits) Ref. 1.21 (0.74–2.00) 0.62 (0.40–0.95) 1.54 (0.45–5.20) 0.75 (0.30–1.85) 0.70 (0.21–2.32) Ref. 0.60 (0.40–0.89) 0.45 (0.26–0.77) 1.56 (1.06–2.38) Ref. Ref. 1.85 (1.20–2.86) 4.29 (2.65–6.95) 10.82 (5.74–20.41)
1.97 (1.35–2.88) Ref. 1.90 (1.18–3.06)
Abbreviations: ART, antiretroviral therapy; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor.
high-income countries range from 23% to 74%, with the largest studies carried out in Australia, New Zealand, the UK, and Belgium [23,24]. Low vitamin D is highly prevalent in the general adult population and among adults with HIV, with reported rates of 68%–89% in the USA [25]. The Women’s Interagency HIV Study found that approximately 87% of women with HIV had low vitamin D status [26]. In the present study, residence in subtropical (as compared with tropical) latitudes and assessment during winter months was associated with low vitamin D status—a finding that is consistent with other studies [11]. Diet and sun exposure are the primary means of acquiring vitamin D. Greater exposure to sunlight correlates with higher vitamin D status because solar ultraviolet B rays convert 7-dehydrocholesterol to pre-vitamin D3, which is then converted to vitamin D3. A study performed in São Paolo, Brazil, among young adults demonstrated that solar exposure was positively associated with vitamin D levels [27]. In addition, physicians had significantly lower vitamin D levels as compared with individuals with other occupations, which probably reflects a difference in sun exposure between occupations. Differences in sun exposure could account for the association in the present multivariable analysis between gainful employment and low vitamin D status. A shorter length of pregnancy was also associated with low vitamin D status. Normal pregnancy affects calcium and vitamin D metabolism in unique ways such that serum calcium and phosphate levels remain the same as in non-pregnant women, but 1,25(OH)2D, calcitonin, and, to some degree, intact parathyroid hormone levels do not. By the third trimester, 1,25(OH)2D reaches levels roughly 3–4 times that of normal pre-pregnancy levels. The rise in 1,25(OH)2D during pregnancy is not, however, accompanied by hypercalcemia. Longitudinal data describing 25(OH)D during normal pregnancy are inconsistent. A large metaanalysis including 20 studies reported no change in 25(OH)D levels between the first trimester and delivery. Other studies [23,28] reported higher levels of 25(OH)D in the third trimester than in the first trimester, whereas another reported the opposite result [29]. In addition, risk for low vitamin D status has been shown to decrease with increasing pregnancy length until approximately 24 weeks among pregnant Tanzanian women with HIV infection [12]. It is also possible that the present association between lower gestational age and low vitamin D
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status is simply reflective of unmeasured vitamin supplementation during pregnancy. Low CD4 cell count and PI-based cART were found to be protective against low vitamin D status in the present study. Although other studies among pregnant women with HIV have not reported the same inverse association between CD4 cell count and vitamin D, one study in Tanzania did find that the risk of low vitamin D status increased with each rise of 100 cells per mm3 in CD8 count [12]. By contrast, one US study of non-pregnant women with HIV infection [26] and another of adults with HIV infection [30] found an inverse association of low vitamin D with CD4 count, and other studies among adults have shown no association at all [25]. The inverse relationship observed between PI-based cART and low vitamin D status is similar to that reported in another study [25], in which exposure to a PI-based regimen was associated with higher 25(OH)D levels. The mechanism is not clear, but studies have shown that PIs—particularly ritonavir—suppress 25- and 1α-hydroxylase, which are critical for 1,25(OH)2D synthesis [31]. The apparent increase in 25(OH)D observed among patients on PI therapy could be due to decreased conversion of 25(OH)D to 1,25(OH)2D. Despite other reports of low vitamin D status with efavirenz use [30], an association with NNRTIbased cART was not observed in the present study. None of the women on NNRTI-based cART in the present cohort received efavirenz, which could explain why this association was not detected. The present study has some limitations. First, there was incomplete collection of data on vitamin D supplementation and food intake during pregnancy. Supplements might have been given more frequently to women later in pregnancy, which might account for the higher 25(OH)D levels observed at later stages, although 25(OH)D levels were not available for each trimester of pregnancy. Second, the Abbott Architect Vitamin D assay could underestimate vitamin D levels by up to 10% when plasma samples are collected in EDTA or sodium citrate tubes [32]. However, in recent studies comparing automated vitamin D immunoassays with liquid chromatography–tandem mass spectrometry—the nominal gold standard—the Abbott Architect assay was found to have coefficients of variation comparable to those of liquid chromatography– tandem mass spectrometry methods (1.9%–6.9% vs 1.6%–6.1%, respectively) [33]. Last, it was not possible to adjust for anthropometric measurements in the regression model owing to the normal weight fluctuations during pregnancy. In conclusion, the present study confirms that rates of low vitamin D status are high among pregnant women with HIV infection, even in sunrich areas. Because low vitamin D during pregnancy has the potential to affect both maternal and child health, further steps are needed to identify whether low maternal vitamin D status is associated with adverse health outcomes among pregnant women with HIV and their children. Further studies may also be warranted to explore the role of cART regimen modification, as well as vitamin D supplementation, among pregnant women with HIV infection. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijgo.2015.01.017.
Acknowledgments The present study was supported by the National Institutes of Health (Eunice Kennedy Shriver NICHD contract N01-HD-3-3345 [2002–2007] and NICHD contract HHSN267200800001C [NICHD control N01-HD-80001] [2007–2012]) and by Abbott Laboratories. J.J. is supported by NICHD K23HD070760. Conflict of interest The authors have no conflicts of interest. The findings and conclusions of the present study are those of the authors and do not
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[17] Kazemi A, Sharifi F, Jafari N, Mousavinasab N. High prevalence of vitamin D deficiency among pregnant women and their newborns in an Iranian population. J Womens Health (Larchmt) 2009;18(6):835–9. [18] Song SJ, Zhou L, Si S, Liu J, Zhou J, Feng K, et al. The high prevalence of vitamin D deficiency and its related maternal factors in pregnant women in Beijing. PLoS One 2013;8(12):e85081. [19] 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(5):646–52. [20] Weinert LS, Reichelt AJ, Schmitt LR, Boff R, Oppermann ML, Camargo JL, et al. Serum vitamin D insufficiency is related to blood pressure in diabetic pregnancy. Am J Hypertens 2014;27(10):1316–20. [21] Oliveri MB, Mautalen CA, Alonso A, Velázquez H, Trouchot HA, Porto R, et al. Nutritional status of vitamin D in mothers and neonates of Ushuaia and Buenos Aires. Medicina (B Aires) 1993;53(4):315–20. [22] Wagner CL, McNeil R, Hamilton SA, Winkler J, Rodriguez Cook C, Warner G, et al. A randomized trial of vitamin D supplementation in 2 community health center networks in South Carolina. Am J Obstet Gynecol 2013;208(2):137.e1–137.e13. [23] Vandevijvere S, Amsalkhir S, Van Oyen H, Moreno-Reyes R. High prevalence of vitamin D deficiency in pregnant women: a national cross-sectional survey. PLoS One 2012;7(8):e43868. [24] Grant CC, Stewart AW, Scragg R, Milne T, Rowden J, Ekeroma A, et al. Vitamin D during pregnancy and infancy and infant serum 25-hydroxyvitamin D concentration. Pediatrics 2014;133(1):e143–53. [25] Dao CN, Patel P, Overton ET, Rhame F, Pals SL, Johnson C, et al. Low vitamin D among HIV-infected adults: prevalence of and risk factors for low vitamin D Levels in a cohort of HIV-infected adults and comparison to prevalence among adults in the US general population. Clin Infect Dis 2011;52(3):396–405. [26] Adeyemi OM, Agniel D, French AL, Tien PC, Weber K, Glesby MJ, et al. Vitamin D deficiency in HIV-infected and HIV-uninfected women in the United States. J Acquir Immune Defic Syndr 2011;57(3):197–204. [27] Maeda SS, Kunii IS, Hayashi L, Lazaretti-Castro M. The effect of sun exposure on 25-hydroxyvitamin D concentrations in young healthy subjects living in the city of São Paulo, Brazil. Braz J Med Biol Res 2007;40(12):1653–9. [28] Cross NA, Hillman LS, Allen SH, Krause GF, Vieira NE. Calcium homeostasis and bone metabolism during pregnancy, lactation, and postweaning: a longitudinal study. Am J Clin Nutr 1995;61(3):514–23. [29] Ardawi MS, Nasrat HA, BA’Aqueel HS. Calcium-regulating hormones and parathyroid hormone-related peptide in normal human pregnancy and postpartum: a longitudinal study. Eur J Endocrinol 1997;137(4):402–9. [30] Welz T, Childs K, Ibrahim F, Poulton M, Taylor CB, Moniz CF, et al. Efavirenz is associated with severe vitamin D deficiency and increased alkaline phosphatase. AIDS 2010;24(12):1923–8. [31] Cozzolino M, Vidal M, Arcidiacono MV, Tebas P, Yarasheski KE, Dusso AS. HIV-protease inhibitors impair vitamin D bioactivation to 1,25-dihydroxyvitamin D. AIDS 2003;17(4):513–20. [32] Abbott Architect System. 25OHD Package Insert. REF 3L52. Abbott Park, IL: Abbott Laboratories; 2011. [33] Farrell CJ, Martin S, McWhinney B, Straub I, Williams P, Herrmann M. State-of-theart vitamin D assays: a comparison of automated immunoassays with liquid chromatography-tandem mass spectrometry methods. Clin Chem 2012;58(3): 531–42.
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CLINICAL ARTICLE
Low vitamin D status among pregnant Latin American and Caribbean women with HIV Infection Jennifer Jao a,b,⁎, Laura Freimanis c, Marisa M. Mussi-Pinhata d, Rachel A. Cohen c, Jacqueline P. Monteiro d, Maria L. Cruz e, Rhoda S. Sperling b, Andrea Branch a, George K. Siberry f, for the NISDI LILAC Protocol 1 a
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA Department of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA Westat, Rockville, MD, USA d Faculdade de Medicina, Universidade de São Paulo, Ribeirão Preto, Brazil e Serviço de Doenças Infecciosas e Parasitárias, Hospital Federal dos Servidores do Estado, Rio de Janeiro, Brazil f Eunice Kennedy Shriver National Institute of Child Health and Human Development, Maternal and Pediatric Infectious Disease Branch, Bethesda, MD, USA b c
a r t i c l e
i n f o
Article history: Received 16 October 2014 Received in revised form 8 January 2015 Accepted 26 March 2015 Keywords: Caribbean HIV Latin America Pregnancy Vitamin D
a b s t r a c t Objective: To evaluate the prevalence and predictors of low vitamin D status among pregnant women with HIV infection. Methods: The present cross-sectional study analyzed repository specimens collected at 12–34 weeks of pregnancy among women enrolled across 17 sites in Latin America and the Caribbean between 2002 and 2009. Logistic regression modeling was used to identify factors associated with low vitamin D status (25-hydroxyvitamin D b30 ng/mL). Results: Among 715 women, 218 (30.5%) were vitamin D deficient (b20 ng/mL) and 252 (35.2%) were insufficient (21–29 ng/mL). Factors associated with low vitamin D status included residence in subtropical latitudes (adjusted odds ratio [aOR] 1.97, 95% confidence interval [CI] 1.35–2.88), assessment during non-summer seasons (autumn: aOR 1.85, 95% CI 1.20–2.86; spring: 4.3, 2.65–6.95; winter: 10.82, 5.74–20.41), employment (aOR 1.56, 95% CI 1.06–2.38), and assessment before 20 weeks of pregnancy (aOR 1.89, 95% CI 1.18–3.06). Factors protective against low vitamin D status were CD4 count below 200 cells per mm3 (aOR 0.45, 95% CI 0.26–0.77) and protease inhibitors (aOR 0.62, 95% CI 0.40–0.95). Conclusion: Low vitamin D status was prevalent among pregnant women with HIV infection. Further studies are warranted to identify the impact of low maternal vitamin D status. © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction The role of vitamin D in preventing complications among adults with HIV infection—e.g. osteoporosis, fractures, diabetes, and even opportunistic infections—has been an increasingly active area of scientific research. Recent studies [1–3] have linked low vitamin D levels among adults with HIV infection with disease progression, subclinical cardiovascular disease, and possibly bone loss. In addition, low vitamin D status in pregnancy has been associated with adverse maternal and neonatal outcomes, such as maternal periodontal disease [4], preeclampsia [5], gestational diabetes [6], small-for-gestational-age birth weight [7], poor infant and childhood skeletal development [8], and early childhood respiratory infections [9].
⁎ Corresponding author at: Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1087, New York, NY 10029, USA. Tel.: +1 212 824 7497; fax: +1 212 824 2317. E-mail address: [email protected] (J. Jao). 1 Members of the NISDI Perinatal Study Group are given in Supplementary Material S1.
The biological effects of vitamin D could be especially relevant for pregnant women because vitamin D is essential for healthy bones, and is also an important immune modulator that enhances both innate and adaptive immune responses while reducing inflammation. However, few studies have examined vitamin D status among pregnant women with HIV infection. The aim of the present study was therefore to describe the prevalence of low vitamin D levels and identify factors associated with this status among pregnant Latin American and Caribbean women infected with HIV. 2. Materials and methods The present cross-sectional study analyzed vitamin D status among pregnant women enrolled in the National Institute of Child Health and Human Development (NICHD) International Site Development Initiative (NISDI) cohort between January 1, 2002, and December 31, 2009. Informed consent was obtained from all enrolled participants. The study was approved by the institutional review boards of the NICHD and Westat, and in-country ethics committees and national review boards (where appropriate).
http://dx.doi.org/10.1016/j.ijgo.2015.01.017 0020-7292/© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
J. Jao et al. / International Journal of Gynecology and Obstetrics 130 (2015) 54–58
From 2002 to 2009, the Eunice Kennedy Shriver NICHD (Bethesda, MD, USA) enrolled a prospective cohort of pregnant women with HIV infection and their neonates into the NISDI Perinatal protocol and Longitudinal Study in Latin American Countries (LILAC) protocol in Latin America and the Caribbean. In total, 17 sites across Argentina, the Bahamas, Brazil, Mexico, Peru, and Jamaica participated. Women at more than 8 weeks of pregnancy were eligible for the Perinatal protocol, whereas those at more than 22 weeks were eligible for the LILAC protocol. Study visits were conducted prepartum (≤2 visits), at delivery, and until 6 months (Perinatal protocol) or 2 years (LILAC protocol) postpartum. Information collected during the maternal study visits included medical history, physical examinations, and laboratory assessments (hematology, flow cytometry assays, HIV RNA level, and biochemistry). In addition, peripheral blood mononuclear cells and plasma specimens were collected from mothers and infants, and stored at −80 °C for potential future studies. The present study population was restricted to Latin American and Caribbean pregnant women with HIV infection who were enrolled for the first time (subsequent pregnancies were not included) in the NISDI Perinatal and/or LILAC protocols and for whom prepartum blood specimens collected between 12 and 34 weeks of pregnancy were available. Only women whose pregnancies resulted in singleton live births of a neonate without HIV infection were included. 25(OH)D is the clinical indicator of vitamin D status and the precursor of the most biologically active form of vitamin D, 1,25dihydroxyvitamin D. Maternal plasma 25-hydroxyvitamin D (25(OH)D) levels were measured in the repository sample with an Abbott Architect chemiluminescent microparticle immunoassay [10] on an Architect i2000SR analyzer (Abbott, Abbott Park, IL, USA), according to the manufacturer’s instructions, at ARUP Laboratories (Salt Lake City, UT, USA). The samples, which had been previously processed and stored in aliquots at −80 °C in a central repository, were shipped frozen and maintained below −80 °C until the time that the vitamin D assay was performed. Vitamin D deficiency was defined as a 25(OH)D level of 20 ng/mL or less, insufficiency as 21–29 ng/mL, and sufficiency as 30 ng/mL or more [11]. Low vitamin D status was defined as vitamin D insufficiency or deficiency (b30 ng/mL). Information was collected on maternal sociodemographics, gestational age, season at the time of vitamin D assessment, substance use during pregnancy, immunological status, and the antiretroviral therapy (ART) regimen received (defined as the regimen taken for ≥28 days before the date of vitamin D assessment) during pregnancy. The latitude category of the site at which women were enrolled was assigned as tropical if the site was located between the Tropic of Cancer (23.4378°N) and the Tropic of Capricorn (23.4378°S) or subtropical if between the tropical circle of latitude (the Tropic of Cancer or Tropic of Capricorn) and the 35th parallel in each hemisphere. Statistical analyses were performed via SAS version 9.3 (SAS Institute, Cary, NC, USA). Prevalence estimates, including 95% confidence intervals (CIs), were calculated by the exact binomial method. Associations of categorical variables with low vitamin D status were evaluated via the Fisher exact test. Variables that were at least marginally associated with low vitamin D status (P ≤ 0.10) were considered candidates for multivariable analysis. Logistic regression modeling was used to identify factors independently associated with low vitamin D status in pregnancy. P b 0.05 was taken to be statistically significant. 3. Results After excluding women enrolled after 35 weeks of pregnancy (n = 177), those without prenatal blood specimens (n = 60), and specimens from repeat pregnancy enrollments (n = 47), 715 pregnant women with HIV infection were included in the present analysis. At the prenatal visit, the mean maternal age was 28.6 ± 5.7 years and the mean length of pregnancy was 25 ± 6.3 weeks. Approximately
55
one-quarter of participants had a gestational age of less than 20 weeks at the time of the vitamin D assessment (Table 1). Overall, 542 (75.8%) women had completed at least 7 years of education. Tobacco use during pregnancy was reported by more than one-fifth of participants and alcohol use by more than 10% (Table 1). Marijuana was the most frequent illicit substance used during pregnancy (2.5%). At enrollment, 113 (15.9%) women had a CD4 count of 200 cells per mm3 or less, and 318 (44.8%) had an HIV RNA level of 1000 copies per mL or higher. Approximately 10% were classified as HIV class C by the US Centers for Disease Control (CDC) classification. A total of 322 (45.1%) women had received three-drug combination ART (cART), whereas 337 (47.1%) had not received ART for at least 28 days at the time of the vitamin D assessment. All non-nucleoside reverse transcriptase inhibitor (NNRTI)-based cART included nevirapine (n = 127), whereas protease inhibitor (PI)-based cART (n = 195) included lopinavir/ritonavir (n = 123), nelfinavir (n = 63), atazanavir (n = 3), fosamprenavir or amprenavir (n = 3), saquinavir (n = 2), or indinavir (n = 1). Eleven (1.5%) women received tenofovir as part of their cART. The mean plasma vitamin D level at the prepartum visit was 25.5 ± 9.8 ng/mL. Overall, 218 (30.5%; 95% CI 27.13%–33.96%) of pregnant women were vitamin D deficient, and an additional 252 (35.2%; 95% CI 31.74%–38.75%) were insufficient. Only 245 (34.3%; 95% CI 30.79%–37.87%) women were sufficient. The mean 25(OH)D levels were 15.3 ± 3.1 ng/mL, 25.0 ± 2.6 ng/mL, and 36.9 ± 6.5 ng/mL among women who were vitamin D deficient, insufficient, and sufficient, respectively. Overall, 470 (65.7%; 95% CI 62.13%–69.21%) women met the criteria for low vitamin D status. The following variables were included in the final logistic regression model: latitude circle of the site, employment status, gestational age, season of vitamin D assessment, CD4 count at enrollment, and ART regimen. Factors associated with increased risk of low vitamin D status in multivariate analysis included residence in subtropical latitudes, vitamin D assessment during a non-summer season, vitamin D assessment after fewer than 20 weeks of pregnancy, and gainful employment (Table 2). Factors associated with decreased risk of low vitamin D status included a CD4 count below 200 cells per mm3 or between 200 and 499 cells per mm3, and receipt of a PI-based cART regimen (Table 2). 4. Discussion There was a high prevalence of vitamin D insufficiency and deficiency among the present cohort of Latin American and Caribbean pregnant women with HIV infection, despite their residence in tropical and subtropical latitudes. Women who lived in subtropical latitudes, were gainfully employed, were at an early stage of pregnancy, and were assessed outside of summer were at increased risk of deficiency, whereas those receiving PI-based cART and with a lower initial CD4 cell count were at decreased risk. The high rates of low vitamin D status observed in the present study are consistent with the few data that have been published so far for pregnant women with HIV infection. For example, in a large Tanzanian study of 884 pregnant women with HIV infection [12], 39% had low vitamin D status (b80 nmol/L or b30 ng/mL), whereas a smaller nested case–control study in India found rates close to 98% [13]. The mean 25(OH)D levels in the present cohort (25.5 ng/mL) were slightly lower but similar to those in the Tanzanian study (35.7 ng/mL), and slightly higher but similar to those in the smaller Indian case–control study (15.25 ng/mL). Low levels of vitamin D are common in pregnancy worldwide. Although definitions of low vitamin D status vary among studies, rates of hypovitaminosis D reported during pregnancy range from 20% to 98% in countries such as The Gambia [14], Brazil [15], Turkey [16], Iran [17], China [18], and South India [19]. One study of 84 pregnant Brazilian adolescents reported that 43% of participants had a 25(OH)D level of less than 50 nmol/L (25 ng/mL) [15], whereas another reported that 86% of pregnant women with gestational diabetes had a 25(OH)D
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J. Jao et al. / International Journal of Gynecology and Obstetrics 130 (2015) 54–58
Table 1 Characteristics of participants by vitamin D levels.a Characteristics
Maternal age at enrollment, y b20 20–29 N29 Length of pregnancy at vitamin D assessment, wk b20 ≥20 Ethnic origin Black Other White Maternal education, y 0–6 7–12 ≥13 Number in household 1–3 ≥4 Gainful employment Tobacco use in pregnancy Alcohol use in pregnancy Crack/cocaine use in pregnancy Marijuana use during pregnancy Reason for ART Prophylaxis Treatment Missing data CD4 count at enrollment, cells per mm3 b50 50–200 201–350 351–500 N500 Missing data CD4% at enrollment b14 14–28 ≥29 Missing data HIV RNA level at enrollment, copies per mL b1000 1000–10 000 ≥10 000 Missing CDC clinical classification at enrollment A B C ART regimen at time of sample (≥28 d) No ART ≥28 d 2 NRTIs and 1 NNRTI 2 NRTIs and 1 PI Dual Mono Other Season when prepartum blood sample obtained Summer Autumn Spring Winter Latitude circle Tropical Subtropical
Vitamin D levels
Odds ratio (95% CI)
P value d
Low b (n = 470)
Sufficient c (n = 245)
Total (n = 715)
20 (4.3) 235 (50.0) 215 (45.7) 24.8 ± 6.5 107 (22.8) 363 (77.2)
17 (6.9) 131 (53.5) 97 (39.6) 25.9 ± 6.0 35 (14.3) 210 (85.7)
37 (5.2) 366 (51.2) 312 (43.6)
0.66 (0.33–1.30) Ref. 1.24 (0.90–1.70)
142 (19.9) 573 (80.1)
1.77 (1.16–2.68) Ref.
81 (17.2) 199 (42.3) 190 (40.4)
53 (21.6) 105 (42.9) 87 (35.5)
134 (18.7) 304 (42.5) 277 (38.7)
0.70 (0.46–1.07) 0.87 (0.61–1.23) Ref.
0.2603
100 (21.3) 339 (72.1) 31 (6.6)
73 (29.8) 160 (65.3) 12 (4.9)
173 (24.2) 499 (69.8) 43 (6.0)
0.53 (0.26–1.10) 0.82 (0.41–1.64) Ref.
0.0383
228 (48.5) 242 (51.5) 135 (28.7) 106 (22.6) 49 (10.4) 19 (4.0) 10 (2.1)
112 (45.7) 133 (54.3) 54 (22.0) 53 (21.6) 32 (13.1) 7 (2.9) 8 (3.3)
340 (47.6) 375 (52.4) 189 (26.4) 159 (22.2) 81 (11.3) 26 (3.6) 18 (2.5)
Ref. 0.89 (0.66–1.22) 0.70 (0.49–1.01) 1.05 (0.73–1.53) 0.77 (0.48–1.25) 1.43 (0.59–3.46) 0.64 (0.25–1.65)
0.5280
196 (42.2) 269 (57.8) 5
82 (34.0) 159 (66.0) 4
278 (39.4) 428 (60.6) 9
Ref. 0.71 (0.51–0.98) –
0.0422
4 (0.9) 63 (13.4) 124 (26.4) 119 (25.4) 159 (33.9) 1
5 (2.0) 41 (16.8) 82 (33.6) 53 (21.7) 63 (25.8) 1
9 (1.3) 104 (14.6) 206 (28.9) 172 (24.1) 222 (31.1) 2
0.32 (0.08–1.22) 0.61 (0.37–0.99) 0.60 (0.40–0.90) 0.89 (0.58–1.38) Ref. –
0.0341
40 (9.9) 191 (47.4) 172 (42.7) 67
19 (9.4) 107 (53.0) 76 (37.6) 43
59 (9.8) 298 (49.3) 248 (41.0) 110
0.93 (0.51–1.71) 0.79 (0.55–1.13) Ref. –
0.4285
258 (55.1) 94 (20.1) 116 (24.8) 2
135 (55.6) 55 (22.6) 53 (21.8) 2
393 (55.3) 149 (21.0) 169 (23.8) 4
Ref. 0.89 (0.60–1.32) 1.15 (0.78–1.68) –
0.5805
407 (86.6) 23 (4.9) 40 (8.5)
195 (79.6) 20 (8.2) 30 (12.2)
602 (84.2) 43 (6.0) 70 (9.8)
Ref. 0.55 (0.30–1.03) 0.64 (0.39–1.06)
0.0456
241 (51.3) 86 (18.3) 107 (22.8) 12 (2.6) 14 (3.0) 10 (2.1)
96 (39.2) 41 (16.7) 88 (35.9) 4 (1.6) 11 (4.5) 5 (2.0)
337 (47.1) 127 (17.8) 195 (27.3) 16 (2.2) 25 (3.5) 15 (2.1)
Ref. 0.84 (0.54–1.30) 0.48 (0.34–0.70) 1.19 (0.38–3.80) 0.51 (0.22–1.16) 0.80 (0.27–2.39)
b0.001
78 (16.6) 127 (27.0) 145 (30.9) 120 (25.5)
88 (35.9) 96 (39.2) 45 (18.4) 16 (6.5)
166 (23.2) 223 (31.2) 190 (26.6) 136 (19.0)
Ref. 1.49 (1.00–2.24) 3.64 (2.31–5.72) 8.46 (4.62–15.48)
b0.001
169 (36.0) 301 (64.0)
129 (52.7) 116 (47.3)
298 (41.7) 417 (58.3)
Ref. 1.98 (1.45–2.71)
b0.001
0.1350
0.0388 b0.001
0.0606 0.8498 0.3203 0.5298 0.4508
Abbreviations: CI, confidence interval; ART, antiretroviral therapy; CDC, Centers for Disease Control; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. a Values are given as number (percentage) or mean ± SD, unless indicated otherwise. b b30 ng/mL. c ≥30 ng/mL. d By t test for continuous variables and χ2 test for categorical variables.
level of less than 30 ng/mL [20]. An even smaller study in Argentina reported that 62% of women had 25(OH)D levels of less than 8 ng/mL at delivery [21]. High-income countries have reported similar rates. In
the USA, for example, the proportion of women with low vitamin D was found to range from 50% to 85% [22], with African Americans and Hispanics at highest risk. Reported rates of low vitamin D in other
J. Jao et al. / International Journal of Gynecology and Obstetrics 130 (2015) 54–58 Table 2 Factors associated with low vitamin D status in pregnancy in logistic regression. Factor
ART lasting ≥28 d at or around vitamin D assessment No ART ≥28 d 2 NRTIs and 1 NNRTI 2 NRTIs and 1 PI Dual Mono Other CD4 cell count at enrollment, cells per mm3 ≥500 200–499 b200 Gainful employment Yes No Season of vitamin D assessment Summer Autumn Spring Winter Latitude circle of site location Tropical Subtropical Length of pregnancy at time of vitamin D assessment, wk ≥20 b20
Adjusted odds ratio (95% Wald confidence limits) Ref. 1.21 (0.74–2.00) 0.62 (0.40–0.95) 1.54 (0.45–5.20) 0.75 (0.30–1.85) 0.70 (0.21–2.32) Ref. 0.60 (0.40–0.89) 0.45 (0.26–0.77) 1.56 (1.06–2.38) Ref. Ref. 1.85 (1.20–2.86) 4.29 (2.65–6.95) 10.82 (5.74–20.41)
1.97 (1.35–2.88) Ref. 1.90 (1.18–3.06)
Abbreviations: ART, antiretroviral therapy; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor.
high-income countries range from 23% to 74%, with the largest studies carried out in Australia, New Zealand, the UK, and Belgium [23,24]. Low vitamin D is highly prevalent in the general adult population and among adults with HIV, with reported rates of 68%–89% in the USA [25]. The Women’s Interagency HIV Study found that approximately 87% of women with HIV had low vitamin D status [26]. In the present study, residence in subtropical (as compared with tropical) latitudes and assessment during winter months was associated with low vitamin D status—a finding that is consistent with other studies [11]. Diet and sun exposure are the primary means of acquiring vitamin D. Greater exposure to sunlight correlates with higher vitamin D status because solar ultraviolet B rays convert 7-dehydrocholesterol to pre-vitamin D3, which is then converted to vitamin D3. A study performed in São Paolo, Brazil, among young adults demonstrated that solar exposure was positively associated with vitamin D levels [27]. In addition, physicians had significantly lower vitamin D levels as compared with individuals with other occupations, which probably reflects a difference in sun exposure between occupations. Differences in sun exposure could account for the association in the present multivariable analysis between gainful employment and low vitamin D status. A shorter length of pregnancy was also associated with low vitamin D status. Normal pregnancy affects calcium and vitamin D metabolism in unique ways such that serum calcium and phosphate levels remain the same as in non-pregnant women, but 1,25(OH)2D, calcitonin, and, to some degree, intact parathyroid hormone levels do not. By the third trimester, 1,25(OH)2D reaches levels roughly 3–4 times that of normal pre-pregnancy levels. The rise in 1,25(OH)2D during pregnancy is not, however, accompanied by hypercalcemia. Longitudinal data describing 25(OH)D during normal pregnancy are inconsistent. A large metaanalysis including 20 studies reported no change in 25(OH)D levels between the first trimester and delivery. Other studies [23,28] reported higher levels of 25(OH)D in the third trimester than in the first trimester, whereas another reported the opposite result [29]. In addition, risk for low vitamin D status has been shown to decrease with increasing pregnancy length until approximately 24 weeks among pregnant Tanzanian women with HIV infection [12]. It is also possible that the present association between lower gestational age and low vitamin D
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status is simply reflective of unmeasured vitamin supplementation during pregnancy. Low CD4 cell count and PI-based cART were found to be protective against low vitamin D status in the present study. Although other studies among pregnant women with HIV have not reported the same inverse association between CD4 cell count and vitamin D, one study in Tanzania did find that the risk of low vitamin D status increased with each rise of 100 cells per mm3 in CD8 count [12]. By contrast, one US study of non-pregnant women with HIV infection [26] and another of adults with HIV infection [30] found an inverse association of low vitamin D with CD4 count, and other studies among adults have shown no association at all [25]. The inverse relationship observed between PI-based cART and low vitamin D status is similar to that reported in another study [25], in which exposure to a PI-based regimen was associated with higher 25(OH)D levels. The mechanism is not clear, but studies have shown that PIs—particularly ritonavir—suppress 25- and 1α-hydroxylase, which are critical for 1,25(OH)2D synthesis [31]. The apparent increase in 25(OH)D observed among patients on PI therapy could be due to decreased conversion of 25(OH)D to 1,25(OH)2D. Despite other reports of low vitamin D status with efavirenz use [30], an association with NNRTIbased cART was not observed in the present study. None of the women on NNRTI-based cART in the present cohort received efavirenz, which could explain why this association was not detected. The present study has some limitations. First, there was incomplete collection of data on vitamin D supplementation and food intake during pregnancy. Supplements might have been given more frequently to women later in pregnancy, which might account for the higher 25(OH)D levels observed at later stages, although 25(OH)D levels were not available for each trimester of pregnancy. Second, the Abbott Architect Vitamin D assay could underestimate vitamin D levels by up to 10% when plasma samples are collected in EDTA or sodium citrate tubes [32]. However, in recent studies comparing automated vitamin D immunoassays with liquid chromatography–tandem mass spectrometry—the nominal gold standard—the Abbott Architect assay was found to have coefficients of variation comparable to those of liquid chromatography– tandem mass spectrometry methods (1.9%–6.9% vs 1.6%–6.1%, respectively) [33]. Last, it was not possible to adjust for anthropometric measurements in the regression model owing to the normal weight fluctuations during pregnancy. In conclusion, the present study confirms that rates of low vitamin D status are high among pregnant women with HIV infection, even in sunrich areas. Because low vitamin D during pregnancy has the potential to affect both maternal and child health, further steps are needed to identify whether low maternal vitamin D status is associated with adverse health outcomes among pregnant women with HIV and their children. Further studies may also be warranted to explore the role of cART regimen modification, as well as vitamin D supplementation, among pregnant women with HIV infection. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijgo.2015.01.017.
Acknowledgments The present study was supported by the National Institutes of Health (Eunice Kennedy Shriver NICHD contract N01-HD-3-3345 [2002–2007] and NICHD contract HHSN267200800001C [NICHD control N01-HD-80001] [2007–2012]) and by Abbott Laboratories. J.J. is supported by NICHD K23HD070760. Conflict of interest The authors have no conflicts of interest. The findings and conclusions of the present study are those of the authors and do not
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