Most pregnant women living with HIV in high-income countries, and now globally through expansion of the Option B+ approach, receive combination antiretroviral therapy (cART), which can reduce the risk of mother-to-child transmission of HIV to <1%.1 As a result of the success in increasing cART coverage in pregnancy, the global number of HIV-exposed uninfected (HEU) children born each year is expected to reach more than 1.5 million.2 In some contexts, HEU children experience a higher risk of poor birth outcomes, linear growth, and neurodevelopment compared with their HIV-unexposed peers.3–5 These poor outcomes may be to attributable to a combination of factors including exposure to HIV and antiretroviral drugs in utero, poorer health and nutritional status of the mother during pregnancy and breastfeeding, deficits in infant immune responses, and socioeconomic factors related to living in an HIV-affected household.4,6
Vitamin D has well-established effects on bone health and calcium homeostasis; however, more recent evidence suggests that vitamin D status in pregnancy may also influence the risk of preeclampsia, gestational diabetes, prematurity, birth weight, postnatal growth, and risk of childhood asthma.7–9 Most published studies on vitamin D in pregnancy, however, are limited to populations of HIV-uninfected mothers.7 In particular, the immunomodulatory and anti-inflammatory effects of vitamin D may affect maternal and child health differently in the context of HIV.10 In terms of evidence on prenatal vitamin D among HIV-infected pregnant women, a cohort study among HIV-infected Tanzanian pregnant women who did not receive cART determined that low vitamin D status in the second trimester (25-hydroxyvitamin D (25(OH)D) concentration <32 ng/mL) was associated with increased risk of maternal HIV progression and incidence of infant stunting and underweight.11,12 In addition, Jao et al13 found that HIV-infected women on cART in Latin America with severe vitamin D deficiency in pregnancy (25(OH)D <10 ng/mL) had increased risk of preterm birth. A small cross-sectional study of pregnant women living with HIV in the United States found that 75% had cord blood plasma 25(OH)D concentrations <20 ng/mL with black, non-Hispanic women having greater risk for low levels than white women.14 To the best of our knowledge, no studies have examined the relationship of prenatal vitamin D status with birth outcomes, growth, and neurodevelopment among HIV-exposed infants in high-income settings.
We therefore performed a prospective cohort study of HIV-infected pregnant women residing in the United States and their HEU infants. We examined the relationship of third trimester vitamin D status with birth outcomes and infant growth and neurodevelopment outcomes at approximately 1 year of age. These results are intended to inform whether trials and studies of vitamin D supplementation in pregnancy should be pursued among HIV-infected women in the United States and similar settings to improve birth outcomes, growth, and neurodevelopment of HEU infants.
This study includes data from a prospective cohort of 257 HIV-infected pregnant women and their HEU infants who were enrolled in the nutrition substudy (R01HD060325) of the parent Surveillance Monitoring for ART Toxicities Study (SMARTT) protocol of the Pediatric HIV/AIDS Cohort Study (PHACS). The substudy recruited pregnant women during 2009–2011 at 15 clinical sites in the United States, including Puerto Rico.15 HIV-infected pregnant women were sequentially enrolled in the study during the second or third trimester of pregnancy, and HEU infants were enrolled at birth. HEU infants were followed up at approximately 1 year of age (9–15 months) for anthropometric and neurodevelopment assessment. The SMARTT protocol and the nutrition substudy were approved by the institutional review board at each recruitment site, at the University of Miami Human Subjects Research Office, and at the Harvard T.H. Chan School of Public Health. Written informed consent was obtained from the mother for herself and her child.
Sociodemographics, Maternal IQ, and Pregnancy Data
At the study visit that occurred after delivery, and as part of the SMARTT protocol, participating mothers were interviewed to obtain data on sociodemographics and assess self-reported substance use during pregnancy. Data on pregnancy history were abstracted from the medical record, including prepregnancy weight (kg) and height (cm), pregnancy and birth complications, gestational age, ART use by trimester, first and last CD4 count and HIV viral load (RNA) in pregnancy, and substance use by trimester of pregnancy. The participant was asked about supplement use in the last 30 days at the time of the first recall. Prepregnancy body mass index (BMI) was calculated as kg/m2. A full-scale maternal intelligence quotient (IQ) was assessed by study staff with the Wechsler16 Abbreviated Scale of Intelligence at the child's 1 year of age visit.
Third Trimester Serum Vitamin D Assessment
Blood was drawn in the third trimester of pregnancy and serum stored at −70°C until the samples were sent to the laboratory of Armando Mendez at the University of Miami Diabetes Research Institute for analysis of 25-hydroxyvitamin D (25(OH)D). 25(OH)D was measured by a competitive protein binding assay couple with electrochemiluminescence detection on a Roche Cobas 6000 analyzer and using manufacturer's reagents (Roche Diagnostics, Indianapolis, IN). This method has been standardized against liquid chromatography–tandem mass spectrometry that in turn has been standardized to the National Institute of Standards and Technology standard and is well correlated with liquid chromatography–tandem mass spectrometry assay.17,18 The assay limit of detection was 3 ng/mL, and inter-assay and intra-assay coefficients of variability were <4% and <6.5%, respectively.
Gestational age at birth was determined by standardized obstetric procedures with dating based on ultrasound in 43% of pregnant women, both ultrasound and clinical findings in 18% using the best obstetric judgment, clinical findings alone in 35%, and 4% were based on last menstrual period or other methods. Preterm birth was defined as gestational age <37 weeks. Birth weight (g) was abstracted from medical record, and the study team used standard techniques to measure length in triplicate within 14 days of birth.19 Small-for-gestational age (SGA) was defined as weight <10th percentile for gestational age by sex using the WHO intergrowth standards.20 Birth length z-scores for age and sex were calculated using WHO reference values for term infants and the Fenton reference for preterm infants.20,21 Apgar scores at 1 and 5 minutes were abstracted from medical records.
Infant Growth and Neurodevelopment
HEU infants were followed up at 12 months of age ±3 months. Infant weight, length, and head circumference measurements were assessed in triplicate using standardized protocols. Length-for-age z-score (LAZ), weight-for-length z-score (WLZ), and weight-for-age z-score (WAZ) were calculated using WHO child growth standards.22 Trained psychologists administered the Bayley23 Scales of Infant and Toddler Development—Third Edition (BSID-III). The BSID-III was only available in English. Infants whose mother/primary caregiver was not able to complete the assessment in English were excluded. The Puerto Rico site did not participate in BSID-III assessments. The cognitive, motor, and language scales were administered through direct interaction with the infant while the socioemotional and adaptive behavior scales were administered as face-to-face interviews with the mother or primary caregiver. BSID-III domain scores were age-standardized with a mean score of 100 and SD of 15.
We defined vitamin D deficiency as 25(OH)D concentrations <20 ng/mL, insufficiency 20–30 ng/mL, and sufficiency as >30 ng/mL.24 First, we examined risk factors for low vitamin D status (either deficiency or insufficiency, 25(OH)D <30 ng/mL) using log-binomial regression models to obtain prevalence ratio estimates.25 We examined the following risk factors for low vitamin D status: maternal age, ethnicity, maternal income, region of residence, third trimester CD4 T-cell count, third trimester HIV-1 RNA copies/mL, third trimester cART regimen, maternal smoking, season of vitamin D blood draw, and vitamin D supplement use. Because of the small sample size and collinearity for some variables, we constructed a parsimonious multivariable model using stepwise variable selection with an entry P value of 0.20 and retained variables with a P value <0.15. We also examine risk factors for 25(OH)D <20 ng/mL as a sensitivity analysis.
We then examined the prospective association of third trimester vitamin D status with birth outcomes and then infant growth and neurodevelopment outcomes at approximately 1 year of age. Linear regression models were fit to examine the relationship of vitamin D status with means of continuous outcomes (birth weight, birth weight z-score, birth length z-score, gestation duration, LAZ, WLZ, WAZ, head circumference-for-age z-score (HCAZ) and BSID-III cognitive, motor, language adaptive behavior, and socioemotional domain scores). These models were implemented using generalized estimating equation models to provide robust variances. Log-binomial models were used to estimate relative risks for the binomial outcomes of preterm birth, SGA, and Apgar score of less than 7 at 1 and 5 minutes. An Apgar score of 7–10 is considered normal with scores 0–6 than indicating increased risk of death and other adverse outcomes.26 Multivariable models included adjustment for maternal age (<25, 25–29.9, 30–34.9, and ≥35 years), maternal race/ethnicity (black non-Hispanic, white non-Hispanic, Hispanic, and multiracial/other), maternal completion of high school (yes/no), maternal income <$10,000 per year (yes/no), region of residence (NY/NJ/Chicago, South, West, Puerto Rico), maternal prepregnancy BMI (<25, 25–29.9, 30–34.9, ≥ 35), third trimester CD4 T-cell count (<350, 350–499, ≥500 cells/mm3), third trimester HIV-1 RNA viral load >400 copies/mL (yes/no), third trimester maternal smoking (yes/no), and child sex (male/female). Multivariable models for Bayley Scales of Infant Development scores were additionally adjusted for maternal IQ (<80, 80–95, ≥95). Because of potential differences in cutoffs to define vitamin D status among individuals of African descent, we present a sensitivity analysis restricted to black non-Hispanic pregnant women.27 We also conducted sensitivity analyses using a 25(OH)D cutoff of >40 ng/mL. All P values were 2-sided with a P value < 0.05 considered statistically significant. Statistical analyses were performed using the SAS v 9.4 (SAS Institute Inc., Cary, NC).
A total of 318 pregnant women were initially considered eligible and consented into the nutrition substudy of the SMARTT. A total of 61 women were excluded from this analysis; 4 due to twin pregnancy, 19 due to no dietary assessment, 15 due to not having a vitamin D assessment, 20 due to having a vitamin D assessment after 37-week gestation, and 3 for other reasons. Therefore, our study population for this analysis consisted of 257 HIV-infected mother-HEU infant pairs who had maternal serum 25(OH)D assessed between 27.0- and 37.0-week gestation (mean 32.0-week gestation). The analysis of BSID-III scores included 170 participants; an additional 87 participants were excluded including 27 participants who resided in Puerto Rico and were not eligible for BSID-III testing as well as 60 mainland US residents who were not assessed.
Characteristics of the study population are presented in Table 1. In terms of ethnicity, 55% of mothers were non-Hispanic black, 35% were Hispanic, 7.1% were non-Hispanic white, and 3.1% were multiracial or of other ethnicity. Most women had an income <$10,000 per year (61.8%). In terms of HIV disease severity and treatment status in the third trimester, 20% of mothers had a CD4 T-cell count <350 cells/mm,3 13% had a HIV-1 RNA concentration >400 copies/mL, and 96% of women received cART during the third trimester. The mean (SD) third trimester serum 25(OH)D concentration was 35.4 (14.2) ng/mL, with a range of 5–79 ng/mL. A total of 38 (15%) women were classified as being vitamin D deficient (<20 ng/mL), 55 (21%) insufficient (20–30 ng/mL), and 164 (64%) were vitamin D sufficient (>30 ng/mL).
Characteristics Associated With Low Third Trimester Vitamin D Status
The association of maternal sociodemographic and pregnancy factors with low vitamin D status (25(OH)D <30 ng/mL) in the third trimester are presented in Table 1, Supplemental Digital Content, http://links.lww.com/QAI/B308. In multivariable models, mothers who resided in New York-New Jersey-Chicago (locations of similar latitude) and the South had 3.99 [95% confidence interval (CI): 1.41 to 11.29] and 3.12 (95% CI: 1.10 to 8.83) times the risk of low vitamin as compared to those residing in the Western United States (P values <0.01). In addition, women who did not take nutritional supplements containing vitamin D had 1.80 (95% CI: 1.01 to 3.20) times the risk of low vitamin D as compared to mothers who took supplements containing ≥400 IU vitamin D/day. Only 8 of the 23 (34.8%) women who did not take vitamin D containing supplements had 25(OH)D concentrations >30 ng/mL. Among women who took daily supplements containing <400 IUs vitamin D, 26 of 45 (58.8%) had 25(OH)D concentrations >30 ng/mL. Women whose blood draw was in the fall/winter seasons seemed to have increased prevalence of low vitamin D status in a univariable analysis [prevalence ratio (PR): 1.48; 95% CI: 1.07 to 2.04], but the results did not reach statistical significance in multivariable models (PR: 1.37; 95% CI: 0.91 to 2.03; P = 0.13). Of note, 0 of 18 white non-Hispanic women in the sample had low vitamin D status, which made relative risks incalculable. In 2 sample comparisons using the Fisher's exact test, white non-Hispanic women had significantly lower prevalence of 25(OH)D <30 ng/mL as compared to both black non-Hispanic (P < 0.01) and Hispanic women (P = 0.01). In a sensitivity analysis, risk factors for 25(OH)D levels <20 ng/mL included not taking nutritional supplements containing vitamin D (PR: 2.67; 95% CI: 1.21 to 5.91) and a HIV viral load >400 copies/mL (PR: 2.44; 95% CI: 1.15 to 5.21).
Vitamin D Status and Birth Outcomes
Univariable and multivariable analyses of third trimester vitamin D status with birth outcomes are presented in Table 2. In multivariable models, both third trimester vitamin D deficiency and insufficiency were associated with 273 g (95% CI: −450 to −97) and 203 g (95% CI: −370 to −35) lower birth weight as compared to vitamin D sufficiency, respectively. Vitamin D deficiency and insufficiency were also associated with lower birth weight z-scores (P values: 0.01 and 0.02, respectively). In addition, third trimester vitamin D deficiency and insufficiency were associated with −0.61 (95% CI: −1.13 to −0.08) and −0.51 (95% CI: −0.94 to −0.08) lower birth length z-scores. Vitamin D deficiency was associated with −0.64-week shorter gestation (95% CI: −1.26 to −0.02) as compared to vitamin D sufficiency, but there was no significant association for insufficiency (mean difference: −0.19 weeks; 95% CI: −0.69 to 0.37). In univariable models, vitamin D deficiency was associated with increased risk of an Apgar score of 7 or less at 1 minute (relative risk: 2.86; 95% CI: 1.08 to 7.55); however, the results did not remain statistically significant in multivariable models.
In a sensitivity analyses restricted to black non-Hispanic women (see Table 2, Supplemental Digital Content, http://links.lww.com/QAI/B308), vitamin D deficiency and insufficiency, defined by <20 and 20–30 ng/mL cutoffs, remained significantly associated with lower birth weight, birth weight z-scores, and birth length as compared to vitamin D sufficiency (>30 ng/mL) (P values <0.05). Vitamin D deficiency also remained associated with shorter duration of gestation among black non-Hispanic women (P < 0.01). We also found no differences in birth outcomes for pregnant women with 25(OH)D levels between 30 and 40 ng/mL and those with >40 ng/mL (see Table 3, Supplemental Digital Content, http://links.lww.com/QAI/B308).
Vitamin D Status and Infant Growth and Neurodevelopment
The association of prenatal vitamin D status with infant anthropometric growth outcomes and BSID-III domain scores are presented in Table 3. In multivariable models, HEU infants who mothers had third trimester vitamin D deficiency had −0.65 (95% CI: −1.18 to −0.13) lower LAZ at 1 year of age as compared to those with vitamin D sufficient mothers (see Table 2, Supplemental Digital Content, http://links.lww.com/QAI/B308). In a sensitivity analyses, vitamin D deficiency remained significantly associated with shorter infant LAZ among black non-Hispanic mothers (P = 0.03), and there was no difference in infant LAZ between those with 25(OH)D concentrations 30–40 and >40 ng/mL (see Tables 2 and 3, Supplemental Digital Content, http://links.lww.com/QAI/B308). We found no statistically significant association of maternal vitamin D status with infant WLZ, WAZ, HCAZ or cognitive, motor, language, adaptive behavior, and socioemotional development at 1 year of age (P values >0.05).
In this prospective cohort study of pregnant women living with HIV in the United States, we found that third trimester vitamin D deficiency (<20 ng/mL) and insufficiency (20–30 ng/mL) were present in 14.8% and 21.4% of women, respectively. Risk factors for low maternal vitamin D status (<30 ng/mL) included residence in New York-New Jersey-Chicago and the South and not taking nutritional supplements containing vitamin D. Black non-Hispanic and Hispanic race women were also at greater risk for low vitamin D status compared with white non-Hispanic women. In terms of birth size, both third trimester vitamin D deficiency and insufficiency were associated with lower birth weights, birth weight z-scores, and birth length z-scores. Vitamin D deficiency was also associated with approximately 4.5-day shorter gestation duration. HEU infants born to mothers with vitamin D deficiency in pregnancy had significantly lower LAZ at 9–15 months of age as compared to infants born to mothers who were vitamin D sufficient. We found no association of maternal vitamin D status with other growth indicators and child neurodevelopment outcomes as assessed by the BSID-III.
Our study adds to the growing body of evidence that suggests that maternal vitamin D status can influence infant size but extends these findings to HIV-infected pregnant women in the United States. We determined that third trimester vitamin D deficiency and insufficiency were robustly associated with lower birth weights, birth weight z-scores, and birth length z-scores. A recent meta-analysis of observational cohort studies of HIV-uninfected women found that pregnancy 25(OH)D concentrations <15 ng/mL were associated with a 131-g deficit in birth weight, whereas a meta-analysis of randomized controlled trials determined that vitamin D supplementation in pregnancy increased infant birth weight by 58 g.7,28 As a result, we hypothesize that based on our study, findings of a 273-g deficit with prenatal 25(OH)D concentrations <20 ng/mL that the relationship of vitamin D status with birth weight may be stronger among HIV-infected women. The mechanisms by which maternal vitamin D status may influence fetal growth remains unclear, but the leading hypotheses include anti-inflammatory, placental vascularization, angiogenesis, and uterine blood flow pathways.29–31
We also found that third trimester vitamin D deficiency was associated with approximately 4.5-day shorter gestation, which may partially explain our birth weight and length findings. A previous cohort study of HIV-infected pregnant women in Latin America enrolled in the NICHD International Site Development Initiative (NISDI) protocol determined that severe vitamin D deficiency (<10 ng/mL) in pregnancy was associated with nearly 5 times the risk of preterm birth as compared to vitamin D sufficiency (≥30 ng/mL).13 In concordance, observational studies among HIV-uninfected women have noted an association between low maternal vitamin D and preterm birth.32 In terms of mechanisms, the strong anti-inflammatory properties of vitamin D may increase gestation length and reduce the risk of preterm birth.33 To the best of our knowledge, there is only one on-going randomized trial of vitamin D supplementation conducted among HIV-infected pregnant women, which intends to examine birth outcomes (NCT02305927). This trial includes 2300 HIV-infected women in Tanzania and will assess the impact on maternal progression of HIV, SGA, and stunting in infancy.34
In addition, we found that prenatal vitamin D deficiency was associated with a relatively large 0.65 z-score deficit in infant length at 1 year of age. Furthermore, vitamin D deficiency also seemed to be associated with a 0.33 z-score deficit in infant head circumference at 1 year, which is also an indicator of skeletal growth, but the results did not reach statistical significance. Previous cohort studies examining the relationship of prenatal 25(OH)D concentrations with child linear growth and head circumference have yielded mixed results. A cohort study of HIV-uninfected pregnant women in the United Kingdom, the Southampton Women's Survey and the Avon Longitudinal Study of Parents and Children, found no association between maternal 25(OH)D in pregnancy with child height at 9 years of age.35 By contrast, a cohort study of HIV-uninfected women in the United States found that prenatal vitamin D levels <30 ng/mL were associated with deficits of 0.13 in LAZ and 0.20 in HCAZ during the first year of life.36 A recent randomized trial of prenatal vitamin D supplementation among HIV-uninfected pregnant women found no effect on child growth. As a result, the relationship of maternal vitamin D status with growth may be stronger in infancy as compared to later childhood or vary by maternal HIV status or setting. In terms of mechanisms, maternal vitamin D status can impact fetal bone development that has been shown to affect infant skeletal growth.37 In support of this mechanism, we found robust associations of prenatal vitamin D status with birth length z-scores, and the magnitude of the association was similar to that for infant LAZ at 1 year of age. Nevertheless, extraskeletal mechanisms are also possible given that maternal vitamin D status in pregnancy can influence the infant immune system and modification of gene expression that can also affect child linear growth.38,39
In addition, although we found that maternal vitamin D status was strongly associated with lower birth weight and birth weight z-scores, there was no association of vitamin D status with WLZ or WAZ at 1 year of age. As a result, catch-up weight gain in early infancy seems to have eliminated the differences in weight seen at birth. These findings are in line with a cohort study of HIV-uninfected mothers in the United States that also found that maternal 25(OH)D levels <30 ng/mL in pregnancy were associated with lower birth weights, but there was no difference in infant BMI at 12 months of age.36 Accelerated weight gain in infancy, which has been documented among HEU infants in the United States, may increase the risk of later life obesity.40,41 Therefore, the pattern of rapid catch-up weight gain experienced by HEU infants born to mothers with vitamin D deficiency or insufficiency in our study may be of concern. A recent study in the United States among HIV-uninfected women determined that prenatal 25(OH)D <15 ng/mL was associated with increased child BMI and waist circumference at 6 years of age.42 Long-term follow-up studies of prenatal vitamin D status with child and adult adiposity and chronic disease risk are needed.
We did not identify a relationship between vitamin D status in pregnancy with infant neurodevelopment as assessed by the BSID-III at 1 year of age. Nevertheless, our sample size of 257 mother-HEU infant pairs is underpowered to detect the small effect sizes that are likely for nutritional exposures in pregnancy (∼0.1 SDs or 1.5 points in age-standardized BSID-III scores).43 However, we did find that vitamin D deficiency in pregnancy was associated with lower birth weight and decreased gestation duration, both of which have evidence for a relationship with poor child development outcomes.44,45 The few observational cohort studies that have examined the relationship of vitamin D status in pregnancy with child development in HIV-uninfected populations have found mixed results.46 Studies in Spain and Australia found vitamin D deficiency in pregnancy was associated with lower child cognitive scores, while studies in the United Kingdom, Denmark, and India determined no association.46 In addition, a study of HIV-uninfected women in the United States found a small positive association between maternal and cord blood 25(OH)D concentration and child IQ at 4–7 years of age.47 No randomized trials of vitamin D supplementation in pregnancy have assessed child neurodevelopment outcomes to date.46 As a result, the relationship of prenatal vitamin D status with child neurodevelopment remains unclear.
This study has several limitations. First, geographic region of residence was highly correlated with ethnicity (ie, 100% of Puerto Rico residents were Hispanic or multiracial), and therefore, it was not possible to completely disentangle these potential risk factors for low vitamin D status. Region of residence likely captured aspects of both ethnicity and sun exposure and therefore resulted in better fit in stepwise selection models over ethnicity alone. In addition, because of the observational design of the study, we cannot rule out residual or unmeasured confounding. As a result, randomized controlled trials of vitamin D supplementation will be needed to determine a causal effect. Furthermore, the relatively small sample size likely led to inadequate power to detect modest effect sizes on child neurodevelopment and binomial outcomes such as preterm birth and SGA. In addition, there is evidence that use of serum 25(OH)D status in the absence of vitamin D binding protein may overestimate vitamin deficiency in black populations and require altered cut-points to define vitamin D status.27 Nevertheless, our results were robust to using 25(OH)D cutoffs of <20 and 20–30 ng/mL to define deficiency and insufficiency among black non-Hispanic women. In addition, relatively few women (n = 88) in our study had circulating 25(OH)D levels >40 ng/mL that are required to optimize production of 1,25(OH)2D during pregnancy, and therefore, we may have underestimated the magnitude of risk for poor birth, growth, and development outcomes associated with low vitamin D levels.48
Overall, this study expands the growing evidence that vitamin D status in pregnancy can influence birth outcomes and infant growth to HEU infants in a high-income setting. Therefore, vitamin D supplementation in pregnancy may reduce the high risk of preterm birth, low birth weight, and linear growth faltering experienced infants born to HIV-infected mothers. Randomized controlled trials of vitamin D supplementation for HIV-infected pregnant women at risk for vitamin D deficiency or insufficiency in the United States and diverse settings are warranted.
The authors thank the children and families for their participation in PHACS, and the individuals and institutions involved in the conduct of PHACS.
The following institutions, clinical site investigators, and staff participated in conducting PHACS SMARTT in 2017, in alphabetical order: Ann & Robert H. Lurie Children's Hospital of Chicago: Ellen Chadwick, Margaret Ann Sanders, Kathleen Malee, and Scott Hunter; Baylor College of Medicine: William Shearer, Mary Paul, Norma Cooper, and Lynnette Harris; Bronx Lebanon Hospital Center: Murli Purswani, Emma Stuard, Mahboobullah Mirza Baig, and Alma Villegas; Children's Diagnostic & Treatment Center: Ana Puga, Dia Cooley, Patricia A. Garvie, and James Blood; New York University School of Medicine: William Borkowsky, Sandra Deygoo, and Marsha Vasserman; Rutgers—New Jersey Medical School: Arry Dieudonne, Linda Bettica, and Juliette Johnson; St. Jude Children's Research Hospital: Katherine Knapp, Kim Allison, Megan Wilkins, and Jamie Russell-Bell; San Juan Hospital/Department of Pediatrics: Nicolas Rosario, Lourdes Angeli-Nieves, and Vivian Olivera; SUNY Downstate Medical Center: Stephan Kohlhoff, Ava Dennie, Ady Ben-Israel, and Jean Kaye; Tulane University School of Medicine: Russell Van Dyke, Karen Craig, and Patricia Sirois; University of Alabama, Birmingham: Marilyn Crain, Paige Hickman, and Dan Marullo; University of California, San Diego: Stephen A. Spector, Kim Norris, and Sharon Nichols; University of Colorado, Denver: Elizabeth McFarland, Emily Barr, Christine Kwon, and Carrie Chambers; University of Florida, Center for HIV/AIDS Research, Education and Service: Mobeen Rathore, Kristi Stowers, Saniyyah Mahmoudi, Nizar Maraqa, and Laurie Kirkland; University of Illinois, Chicago: Karen Hayani, Lourdes Richardson, Renee Smith, and Alina Miller; University of Miami: Gwendolyn Scott, Sady Dominguez, Jenniffer Jimenez, and Anai Cuadra; Keck Medicine of the University of Southern California: Toni Frederick, Mariam Davtyan, Guadalupe Morales-Avendano, and Janielle Jackson-Alvarez; University of Puerto Rico School of Medicine, Medical Science Campus: Zoe M. Rodriguez, Ibet Heyer, and Nydia Scalley Trifilio.
1. Joint United Nations Programme on HIV/AIDS. Ending AIDS: Progress towards the 90-90-90 Targets. Geneva, Switzerland: UNAIDS; 2017.
2. Joint United Nations Programme on HIV/AIDS. Progress Report on the Global Plan Towards the Elimination of New HIV Infections Among Children by 2015 and Keeping Their Mothers Alive. Geneva, Switzerland: UNAIDS; 2013.
3. Rice ML, Russell JS, Frederick T, et al. Risk for speech and language impairments in pre-school aged HIV-exposed uninfected children with in utero combination antiretroviral exposure. Pediatr Infect Dis J. 2018;37:678–685.
4. Filteau S. The HIV-exposed, uninfected African child. Trop Med Int Health. 2009;14:276–287.
5. Locks LM, Manji KP, Kupka R, et al. High burden of morbidity and mortality but not growth failure in infants exposed to but uninfected with HIV in Tanzania. J Pediatr. 2017;180:191–199.e192.
6. Afran L, Garcia Knight M, Nduati E, et al. HIV-exposed uninfected children: a growing population with a vulnerable immune system? Clin Exp Immunol. 2014;176:11–22.
7. Roth DE, Leung M, Mesfin E, et al. Vitamin D supplementation during pregnancy: state of the evidence from a systematic review of randomised trials. BMJ. 2017;359:j5237.
8. De-Regil LM, Palacios C, Ansary A, et al. Vitamin D supplementation for women during pregnancy. Cochrane Database Syst Rev. 2012;14:CD008873.
9. Wagner CL, Hollis BW, Kotsa K, et al. Vitamin D administration during pregnancy as prevention for pregnancy, neonatal and postnatal complications. Rev Endocr Metab Disord. 2017;18:307–322.
10. Baeke F, Takiishi T, Korf H, et al. Vitamin D: modulator of the immune system. Curr Opin Pharmacol. 2010;10:482–496.
11. Finkelstein JL, Mehta S, Duggan C, et al. Maternal vitamin D status and child morbidity, anemia, and growth in human immunodeficiency virus-exposed children in Tanzania. Pediatr Infect Dis J. 2012;31:171–175.
12. Mehta S, Giovannucci E, Mugusi FM, et al. Vitamin D status of HIV-infected women and its association with HIV disease progression, anemia, and mortality. PLoS One. 2010;5:e8770.
13. Jao J, Freimanis L, Mussi-Pinhata MM, et al. Severe vitamin D deficiency in HIV-infected pregnant women is associated with preterm birth. Am J Perinatol. 2017;34:486.
14. Eckard AR, Leong T, Avery A, et al. Short communication: high prevalence of vitamin D deficiency in HIV-infected and HIV-uninfected pregnant women. AIDS Res Hum Retroviruses. 2013;29:1224–1228.
15. Miller TL, Jacobson DL, Somarriba G, et al. A multicenter study of diet quality on birth weight and gestational age in infants of HIV-infected women. Matern Child Nutr. 2017;13. doi: 10.1111/mcn.12378. [epub 2016 Nov 8].
16. Wechsler D. Wechsler Adult Intelligence Scale–Fourth Edition (WAIS–IV). San Antonio, TX: The Psychological Corporation; 2008.
17. Knudsen CS, Nexo E, Højskov CS, et al. Analytical validation of the Roche 25-OH vitamin D total assay. Clin Chem Lab Med. 2012;50:1965–1968.
18. Emmen JM, Wielders JP, Boer AK, et al. The new Roche Vitamin D Total assay: fit for its purpose? Clin Chem Lab Med. 2012;50:1969–1972.
19. Jacobson DL, Patel K, Siberry GK, et al. Body fat distribution in perinatally HIV-infected and HIV-exposed but uninfected children in the era of highly active antiretroviral therapy: outcomes from the Pediatric HIV/AIDS Cohort Study. Am J Clin Nutr. 2011;94:1485–1495.
20. Villar J, Cheikh Ismail L, Victora CG, et al. International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project. Lancet. 2014;384:857–868.
21. Fenton TR, Sauve RS. Using the LMS method to calculate z-scores for the Fenton preterm infant growth chart. Eur J Clin Nutr. 2007;61:1380–1385.
22. Onis M. WHO child growth standards based on length/height, weight and age. Acta Paediatr Suppl. 2006;450:76–85.
23. Bayley N. Bayley Scales of Infant and Toddler Development: Bayley-III. San Antonio, TX: Harcourt Assessment, Psych. Corporation; 2006.
24. Ross AC, Taylor CL, Yaktine AL, et al. Institute of medicine (US) committee to review dietary reference intakes for vitamin D and calcium. In: Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press; 2011.
25. Wacholder S. Binomial regression in GLIM: estimating risk ratios and risk differences. Am J Epidemiol. 1986;123:174–184.
26. Apgar V, Holaday DA, James LS, et al. Evaluation of the newborn infant; second report. J Am Med Assoc. 1958;168:1985–1988.
27. Powe CE, Evans MK, Wenger J, et al. Vitamin D–binding protein and vitamin D status of black Americans and white Americans. N Engl J Med. 2013;369:1991–2000.
28. Aghajafari F, Nagulesapillai T, Ronksley PE, et al. Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies. BMJ. 2013;346:f1169.
29. Liu NQ, Kaplan AT, Lagishetty V, et al. Vitamin D and the regulation of placental inflammation. J Immunol. 2011;186:5968–5974.
30. Gernand AD, Simhan HN, Caritis S, et al. Maternal vitamin D status and small-for-gestational-age offspring in women at high risk for preeclampsia. Obstet Gynecol. 2014;123:40–48.
31. Chen Y, Zhu B, Wu X, et al. Association between maternal vitamin D deficiency and small for gestational age: evidence from a meta-analysis of prospective cohort studies. BMJ Open. 2017;7:e016404.
32. Wei SQ, Qi HP, Luo ZC, et al. Maternal vitamin D status and adverse pregnancy outcomes: a systematic review and meta-analysis. J Matern Fetal Neonatal Med. 2013;26:889–899.
33. Christiaens I, Zaragoza DB, Guilbert L, et al. Inflammatory processes in preterm and term parturition. J Reprod Immunol. 2008;79:50–57.
34. Sudfeld CR, Manji KP, Duggan CP, et al. Effect of maternal vitamin D 3 supplementation on maternal health, birth outcomes, and infant growth among HIV-infected Tanzanian pregnant women: study protocol for a randomized controlled trial. Trials. 2017;18:411.
35. Gale CR, Robinson SM, Harvey NC, et al. Maternal vitamin D status during pregnancy and child outcomes. Eur J Clin Nutr. 2008;62:68–77.
36. Eckhardt CL, Gernand AD, Roth DE, et al. Maternal vitamin D status and infant anthropometry in a US multi-centre cohort study. Ann Hum Biol. 2015;42:217–224.
37. Mahon P, Harvey N, Crozier S, et al. Low maternal vitamin D status and fetal bone development: cohort study. J Bone Miner Res. 2010;25:14–19.
38. Hossein-nezhad A, Holick MF. Optimize dietary intake of vitamin D: an epigenetic perspective. Curr Opin Clin Nutr Metab Care. 2012;15:567–579.
39. Lange NE, Litonjua A, Hawrylowicz CM, et al. Vitamin D, the immune system and asthma. Expert Rev Clin Immunol. 2009;5:693–702.
40. Neri D, Somarriba GA, Schaefer NN, et al. Growth and body composition of uninfected children exposed to human immunodeficiency virus: comparison with a contemporary cohort and United States National Standards. J Pediatr. 2013;163:249–254; e241–242.
41. Ong KK, Loos RJ. Rapid infancy weight gain and subsequent obesity: systematic reviews and hopeful suggestions. Acta Paediatr. 2006;95:904–908.
42. Daraki V, Roumeliotaki T, Chalkiadaki G, et al. Low maternal vitamin D status in pregnancy increases the risk of childhood obesity. Pediatr Obes. 2018;13:467–475.
43. Larson LM, Yousafzai AK. A meta-analysis of nutrition interventions on mental development of children under-two in low-and middle-income countries. Matern Child Nutr. 2017;13. doi: 10.1111/mcn.12229. [epub 2015 Nov 26].
44. Aarnoudse-Moens CSH, Weisglas-Kuperus N, van Goudoever JB, et al. Meta-analysis of neurobehavioral outcomes in very preterm and/or very low birth weight children. Pediatrics. 2009;124:717–728.
45. Shenkin SD, Starr JM, Deary IJ. Birth weight and cognitive ability in childhood: a systematic review. Psychol Bull. 2004;130:989–1013.
46. Larqué E, Morales E, Leis R, et al. Maternal and foetal health implications of vitamin D status during pregnancy. Ann Nutr Metab. 2018;72:179–192.
47. Keim SA, Bodnar LM, Klebanoff MA. Maternal and cord blood 25(OH)-vitamin D concentrations in relation to child development and behaviour. Paediatr Perinat Epidemiol. 2014;28:434–444.
48. Hollis BW, Wagner CL. Vitamin D and pregnancy: skeletal effects, nonskeletal effects, and birth outcomes. Calcif Tissue Int. 2013;92:128–139.