Preterm delivery (PTD) is the most important cause of neonatal morbidity and mortality worldwide.1 Globally, including the US, Women living with HIV (WLHIV) have higher rates of PTD compared with the general population (12%–19% vs. 7%–12%).2,3 The risk of PTD in WLHIV is further increased by the use of protease inhibitors (PI)–containing antiretroviral treatment (ART) during pregnancy, particularly when PI-containing ART is initiated before or during the first trimester of pregnancy.4–14
The pathogenesis of PTD is incompletely understood and is probably multifactorial, but maternal, fetal, systemic, and local inflammatory changes play a central role.15–30 Parturition is normally triggered by inflammation, both in the context of normal-term delivery (TD) and spontaneous PTD (SPTD). However, women with SPTD exhibit earlier and exacerbated inflammatory signals during pregnancy, including elevations in multiple inflammatory cytokines and chemokines that are also increased by HIV infection, which suggests a potential link between HIV infection and SPTD.31–41
Vitamin D deficiency, which has been commonly reported in individuals living with HIV, has also been associated with increased activity of inflammatory diseases.42–44 Vitamin D also potentiates the immunoregulatory effect of estradiol,44 but studies on the association of vitamin D deficiency with pregnancy outcomes of HIV-uninfected women have yielded mixed results.45–52 However, the lack of a consensus definition of vitamin D deficiency and of standards for what constitutes optimal levels of vitamin D during pregnancy may have contributed to the heterogeneity of the results.53,54
The primary objective of this study was to identify soluble plasma markers of inflammation, immune activation, and regulation associated with increased risk of SPTD in WLHIV. In addition, we evaluated whether the timing of PI-containing ART initiation, and vitamin D levels in WLHIV were associated with plasma inflammatory factors in the context of SPTD.
This was an exploratory case-control study of WLHIV enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) protocol 1025 (P1025), a US-based, multi-site, prospective study that enrolled WLHIV and their infants between 2003 and 2013.13 Eligible for inclusion in this analysis were participants with a live singleton birth. Women with delivery occurring at ≤35 and ≥37 weeks gestation constituted the cases and the controls, respectively. Cases and controls were included if they met the following criteria: had ≥2 mL plasma collected ≥1 week before delivery, did not receive immunosuppressive medication or blood products within 2 weeks before sample collection, and did not have infants with major structural abnormalities, trisomies, and conditions associated with polyhydramnios. For women with multiple pregnancies in P1025, the most recent eligible pregnancy was retained in the analysis. All eligible cases were included in the analysis. Controls were selected randomly to matched cases at a 2:1 ratio on race (Black vs. non-Black) and gestational age at the time of plasma collection (14–20 vs. 21–27 vs. 28–34 weeks). The sample size and the case: control ratio were chosen to achieve 80% power to detect differences ≥1 SD between cases and controls with α = 0.05. Figure S1, Supplemental Digital Content, https://links.lww.com/QAI/B346 shows the study derivation.
High sensitivity (hs) IL-6, hsIL-8, hsIL-10, hsIL-1β, G-CSF, MCP-1, IP-10, GM-CSF, GROα, IFNγ, IL-17A, vascular endothelial factor a, and TNFα were measured using a multiplex array chemiluminescence custom kit (EMD Millipore Temecula, CA) and the following factors by ELISA: TGFβ (R&D Systems Minneapolis, MN), IL-18 (eBiosciences San Diego, CA), sIL-2Rα (EMD Millipore), sCD14 (R&D Systems), and MMP9 (EMD Millipore). Assays were performed per manufacturers' instructions.
Eicosanoids were quantified by iC42 Clinical Research and Development (Aurora, CO) using liquid chromatography–tandem mass spectrometry assays: Prostaglandin (PG)-D2, PG-E2, PG-F2, PG-J2, PG-Delta-12, PG-15-deoxy-D2, PG-8-Isoprostane,55,56 as well as 9-HODE, 13-HODE, 5-HEPE, 8-HEPE, 9-HETE, 11-HETE, 12-HETE, and 15-HETE.57
25OH-Vitamin D was measured by antibody competitive immunoassay using the ADVIA Centaur kit as per manufacturer's instructions.
Log10-based transformation was performed for all biomarkers to approximate a normal distribution. Multivariable conditional logistic regression models were built, taking into account matching between cases and controls, to evaluate associations of each biomarker concentration with SPTD. Weighted linear regression models accounting for the sampling fraction of cases and controls from the underlying eligible P1025 study population were used to evaluate associations of HIV RNA at/before plasma sample collection (≤400 vs. >400 copies/mL), time of initiating PI-containing ART regimen before plasma sample collection (first trimester or earlier vs. second/third trimester vs. no PI-containing ART), and vitamin D plasma concentration with biomarkers that were associated with SPTD at an overall P-value ≤ 0.1. Vitamin D was evaluated both as a continuous and categorical (<20 vs. ≥20 ng/mL) exposure. Preselect covariates, including alcohol and recreational drug use during pregnancy, obesity, sexually transmitted diseases, and other genital or systemic infections during pregnancy, last CD4 count and HIV plasma RNA at/before plasma sample collection, and CDC class C were included in multivariable models.
Demographic and HIV Disease Characteristics of the Study Population
We obtained samples from 308 WLHIV, including 103 with SPTD. The mean age of participants was 29 years; 58% were Black and 33% were Hispanic (see Table S1, Supplemental Digital Content, https://links.lww.com/QAI/B346). A higher proportion of women with SPTD than TD met CDC HIV category C criteria (25% vs. 12%) and initiated PI-containing ART in the ≤first trimester of pregnancy (37% vs. 31%). Conversely, a lower proportion of women with SPTD had plasma HIV RNA ≤400 copies/mL at the time when the soluble markers were measured (65% vs. 82%). Other parameters were similar in participants with SPTD and TD.
Plasma Factors Associated With SPTD
Among all factors (see Table S2, Supplemental Digital Content, https://links.lww.com/QAI/B346), sCTLA-4, Leukotriene-B4, and Leukotriene-E4 were detected only in 12%–20% of the samples and were excluded from subsequent analyses. For IFNγ, IL-17, vascular endothelial factor a, PG-J2, and vitamin D, <75% participants had quantifiable values. These factors were analyzed as categorical variables.
After adjusting for preselected SPTD risk factors, higher sIL2Rα showed significant associations with increased risk of SPTD (adjusted odds ratio = 2.97, 95% confidence interval: 1.32 to 6.69; Fig. 1) and marginally significant associations for higher sCD14, granulocyte colony stimulating factor (GCSF), PGF2α, and 5-HEPE (adjusted odds ratio of 1.54–4.05; P of 0.08–0.1; Fig. 1).
Association of HIV RNA, PI Use During Pregnancy, and Vitamin D Levels With Markers of SPTD
Based on our previous findings showing a strong correlation of PI use ≤first trimester with SPTD,58 we divided the PI users by the time when they started PI-containing ART. Likewise, we stratified women according to vitamin D insufficiency (vitamin D <20 ng/mL) and plasma HIV RNA ≤400 copies/mL. Table 1 shows that PI, vitamin D, and plasma HIV RNA were not associated with sIL2Rα. ART without PI and plasma HIV RNA >400 copies/mL were associated with lower GCSF levels. Initiation of PI-containing ART ≤first trimester was significantly associated with higher levels of the anti-inflammatory 5-HEPE. Low vitamin D levels were associated with lower plasma levels of 5-HEPE and higher levels of the proinflammatory PG-F2α and moderately associated with higher levels of sCD14.
Association of PI-Containing ART and of Vitamin D Levels With Plasma Eicosanoids
To further understand the associations between the use of PI and of vitamin D deficiency with PGF-2α and 5-HEPE plasma levels during pregnancy, we performed a post-hoc analysis of the associations of all quantifiable eicosanoids with the use of PI and vitamin D. The data showed that compared with participants who initiated PI-containing ART >first trimester of pregnancy or did not use PI had lower levels of anti-inflammatory eicosanoids, including 9-HODE, 13-HODE, 5-HEPE, 8-HEPE, 9-HETE, 11-HETE, 12-HETE, and 15-HETE (see Table S3, Supplemental Digital Content, https://links.lww.com/QAI/B346). Vitamin D levels were negatively associated with proinflammatory and myometrium-activating prostaglandins, including PG-D2, PG-Delta12, PG-F2α, and PG-8-isoprostane and positively associated with levels of the anti-inflammatory eicosanoids 5- and 8-HEPE.
The primary objective of this study was to identify plasma factors that could recognize WLHIV at highest risk of SPTD. sIL2Rα was the best predictor of increased risk of SPTD, independent of CD4 cell counts, HIV plasma RNA, and other established risk factors for SPTD. Specifically, for each pg/mL increase in sIL2Rα plasma concentration, there was a 3-fold increase in the odds of SPTD. Our findings are in accordance with previous results in women without HIV.32,59 IL2Rα or CD25 is a marker of T-cell activation, which is also expressed by regulatory T cells. Its association with SPTD suggests a role of T-cell activation in the pathogenesis of SPTD. Along the same lines, Fiore et al60 showed increased levels of IL2 production during pregnancy in WLHIV who experienced SPTD and who also received effective ART and concluded that ART-associated immune reconstitution may be causally associated with SPTD. More studies are needed to fully understand the mechanism of the association of sIL2Rα levels with SPTD. Nevertheless, sIL2Rα is a candidate for screening high-risk women to identify those who may benefit from an intervention to prevent SPTD.
It is interesting to note that high sCD14 and GCSF, which reflect increased bacterial translocation and monocyte activation, respectively, in people living with HIV,31,61,62 were only marginally associated with the odds of SPTD. Collectively, these observations emphasize the potential mechanistic role of T-cell activation in the pathogenesis of SPTD in WLHIV.
Although many studies have identified the use of PI as a risk factor of SPTD in WLHIV, the mechanism underlying this association is incompletely understood. Serghides et al showed that PI-based ART during pregnancy was associated with lower levels of progesterone compared with efavirenz in humans and mice.63,64 Here, we showed that longer use of PI was associated with higher levels of eicosanoids derived from the metabolism of omega-3 and omega-6 polyunsaturated fatty acids, including 5-HEPE, which was a predictor of SPTB in our study.65,66 Members of the cytochrome P450 (CYP) are involved in the metabolism of eicosanoids and it is possible that PI modify the activity of these enzymes in the same way as they affect CYP3A and CYP3B. The effect of 5-HEPE on uterine contractility has not been studied and, therefore, it is possible that its association with SPTD is nonmechanistic.
The effect of vitamin D insufficiency or supplementation in pregnancy is controversial,45–50,52,54,67–70 but its anti-inflammatory activity suggests a potential mechanism for its effect on pregnancy outcomes associated with increased inflammation, such as SPTD, pre-eclampsia, and intrauterine growth retardation. We also found that women with low vitamin D levels had higher inflammatory and uterine contraction-inducing prostaglandins and lower anti-inflammatory eicosanoids. Furthermore, WLHIV and black women, both of whom are at high risk for SPTD, commonly have vitamin D insufficiency.71,72
A limitation of our study was the low number of women on ART without PI [60 out of 308 (19%) participants in this study], characteristic of the treatment landscape in the US at the time when the parent study was conducted. Our sample size was also too low to establish correlations between the duration of PI-containing ARV or the levels of vitamin D with SPTD. Cognizant that our sample size was insufficient to detect associations of PI use or vitamin D insufficiency with SPTD, we formulated our secondary objective, which was to evaluate the associations of PI use or vitamin D levels with SPTD biomarkers.
In conclusion, this study identified sIL2Rα as a potential screening tool to assess the risk of SPTD in WLHIV. It also suggested that anti-inflammatory therapy with a cyclooxygenase inhibitor, such as aspirin, which is currently being studied in women without HIV, may also benefit the WLHIV.73–81
The authors thank Kelly Richardson and Jennifer Canniff for technical support. The following IMPAACT sites participated in P1025: University of Medicine and Dentistry of New Jersey (UMDNJ)-New Jersey Medical School, Department of Pediatrics, Division of Allergy, Immunology and Infectious Diseases: Charmane Calilap-Bernardo, RN, James Oleske, MD, MPH, Jocelyn Grandchamp, RN; Boston Medical Center, Division of Pediatric Infectious Diseases: Mark Mirochnick, MD, Desiree Jones, RN; David Geffen School of Medicine at University of California, Los Angeles (UCLA)-Department of Pediatrics, Division of Infectious Diseases: Maryanne Dillon, BSN, Audra Deveikis, MD; Long Beach Memorial Medical Center, Miller Children's Hospital: Susan Marks, RN, Audra Deveikis, MD; Harbor-UCLA Medical Center-Department of Pediatrics, Division of Infectious Diseases: Margaret A. Keller, MD, Spring Wettgen, RN, PNP; University of Maryland Medical Center, Division of Pediatric Immunology and Rheumatology: John Farley, MD, MPH, Georgine Price, BSN, MPH; Texas Children's Hospital, Allergy and Immunology Clinic: Chivon D. Jackson, RN, BSN, Hunter A. Hammill, MD; Children's Memorial Hospital-Department of Pediatrics, Division of Infectious Disease: Brenda Wolfe, RN, CNS, ACRN, Jessica Shore, RN, BSN; Cook County Hospital: Maureen Haak, RN, MS, James B. McAuley, MD, MPH; University of Chicago-Department of Pediatrics, Division of Infectious Disease: Linda Walsh, MP, John Marcinak, MD; Mount Sinai Hospital Medical Center, Chicago, Women's and Children's HIV Program: Daniel Johnson, MD, Dominika Kowalski, RN, Brenda Wolfe, CNS; Columbia University Medical Center, Pediatric AIDS Clinical Trial Unit (ACTU): Diane Tose, CNM, Seydi Vazquez, RN, MSN; University of Miami Miller School of Medicine, Division of Pediatric Immunology and Infectious Diseases: Charles Mitchell, MD, Gwendolyn B. Scott, MD; University of California San Francisco, School of Medicine, Department of Pediatrics: Diane Wara, MD, Maureen Shannon, FNP, PhD; University of California San Diego, Mother, Child and Adolescent HIV Program: Andrew D. Hull, MD, Mary Caffery, RN, MSN, Linda Proctor, RN, MSN, CNM; Duke University School of Medicine-Department of Pediatrics, Children's Health Center: Kareema Whitfield, BSW, CRC, Felicia Wiley, RN; New York University, School of Medicine, Division of Pediatric Infectious Diseases: Maryam Minter, RN, Sandra Deygoo; Jacobi Medical Center: David Garry, DO, Mindy Katz, MD, Raphaelle Auguste, RN; University of Washington, School of Medicine-Children's Hospital and Regional Medical Center: Jane Hitti, MD, MPH, Michele Acker, PNP; University of Illinois College of Medicine at Chicago, Department of Pediatrics: Mark Vajaranant, MD, Harriett Wittert, RN; San Juan City Hospital: Midnela Acevedo, MD, Elvia Perez, RN; Yale University School of Medicine-Department of Pediatrics, Division of Infectious Disease: Warren A. Andiman, MD, B. Joyce Simpson, RN, MPH; State University of New York (SUNY) at Stony Brook School of Medicine, Division of Pediatric Infectious Diseases: Sharon Nachman, MD, Jennifer Griffin, NP; Wayne State University, School of Medicine, Children's Hospital of Michigan: Theodore Jones, MD, Ellen Moore, MD; Howard University Hospital, Department of Pediatrics and Child Health: Sohail Rana, MD, Caroline Reed, MSN; LA County/University of Southern California, Medical Center: Ana Melendrez, RN, LaShonda Spencer, MD; University of Florida Health Science Center Jacksonville, Division of Pediatric Infectious Disease and Immunology: Mobeen H. Rathore, MD, Isaac Delke, MD; Children's Hospital-University of Colorado at Denver and Health Sciences Center, Pediatric Infectious Diseases (This research was supported by Grant Number MO1 RR00069, General Clinical Research Centers Program, National Center for Research Resources, NIH): A.W., MD, Carol Salbenblatt, MSN; North Broward Hospital District, Children's Diagnostic and Treatment Center: Ana M. Puga, MD, Guillermo Talero, MD, Amy Inman, BS; St. Jude Children's Research Hospital, Department of Infectious Diseases: Edwin Thorpe, Jr, MD, Nina K. Sublette, RN, MSN, FNP; University of Puerto Rico, U. Children's Hospital AIDS: Ruth Santos, RN, Irma Febo, MD; Bronx-Lebanon Hospital Center, Infectious Diseases: Mavis Dummitt, RN, Mirza Baig, MD; University of Massachusetts Memorial Children's Medical School, Department of Pediatrics: Katherine Luzuriaga, MD, Sharon Cormier, RN; Baystate Health, Baystate Medical Center: Barbara W. Stechenberg, MD, Eileen Theroux, RN, BSN; Tulane University Health Sciences Center: Chi Dola, MD; LSU Health Sciences Center: Robert Maupin, MD; University of Alabama at Birmingham, Department of Pediatrics, Division of Infectious Diseases: Robert Pass, MD, Marilyn Crain, MD, MPH.
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