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Clinical Science

Brief Report: Markers of Spontaneous Preterm Delivery in Women Living With HIV: Relationship With Protease Inhibitors and Vitamin D

Weinberg, Adriana MDa; Huo, Yanling MSb; Kacanek, Deborah ScDb; Patel, Kunjal DSc, MPHb; Watts, D. Heather MDc; Wara, Diane MDd; Hoffman, Risa M. MD, PhDe; Klawitter, Jelena PhDf; Christians, Uwe MD, PhDf; for IMPAACT P1025 Team

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: October 1, 2019 - Volume 82 - Issue 2 - p 181-187
doi: 10.1097/QAI.0000000000002111

Abstract

INTRODUCTION

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.

METHODS

Study Design

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.

Soluble Factors

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

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

25OH-Vitamin D was measured by antibody competitive immunoassay using the ADVIA Centaur kit as per manufacturer's instructions.

Statistical Analysis

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.

RESULTS

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).

F1
FIGURE 1.:
Adjusted associations of cytokines, chemokine biomarkers, and vitamin D plasma concentration levels with PTD. Data were derived from 103 WLWH with SPTD and 205 matched controls with TD. Odds ratios >1 indicate the increase in risk of SPTD with each unit increase of the variable. The model was adjusted for 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. A, Shows results for soluble cytokines; (B) shows results for eicosanoids.

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.

T1
TABLE 1.:
Adjusted Associations of Viral Suppression, Time of Initiating PI-Containing ART, and 25OH-Vitamin D Levels With Selected Biomarkers

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.

DISCUSSION

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

ACKNOWLEDGMENTS

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.

REFERENCES

1. Available at: http://www.cdc.gov/reproductivehealth/MaternalInfantHealth/PretermBirth.htm. Accessed March 1, 2018.
2. Venkatesh KK, Morrison L, Livingston EG, et al. Changing patterns and factors associated with mode of delivery among pregnant women with human immunodeficiency virus infection in the United States. Obstet Gynecol. 2018;131:879–890.
3. Blencowe H, Cousens S, Oestergaard MZ, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012;379:2162–2172.
4. Cohan D, Natureeba P, Koss CA, et al. Efficacy and safety of lopinavir/ritonavir versus efavirenz-based antiretroviral therapy in HIV-infected pregnant Ugandan women. AIDS. 2015;29:183–191.
5. Koss CA, Natureeba P, Plenty A, et al. Risk factors for preterm birth among HIV-infected pregnant Ugandan women randomized to lopinavir/ritonavir- or efavirenz-based antiretroviral therapy. J Acquir Immune Defic Syndr. 2014;67:128–135.
6. Kourtis AP, Schmid CH, Jamieson DJ, et al. Use of antiretroviral therapy in pregnant HIV-infected women and the risk of premature delivery: a meta-analysis. AIDS. 2007;21:607–615.
7. Kumar RM, Uduman SA, Khurranna AK. Impact of maternal HIV-1 infection on perinatal outcome. Int J Gynaecol Obstet. 1995;49:137–143.
8. Lopez M, Figueras F, Hernandez S, et al. Association of HIV infection with spontaneous and iatrogenic preterm delivery: effect of ART. AIDS. 2012;26:37–43.
9. Marazzi MC, Liotta G, Nielsen-Saines K, et al. Extended antenatal antiretroviral use correlates with improved infant outcomes throughout the first year of life. AIDS. 2010;24:2819–2826.
10. Martin F, Taylor GP. Increased rates of preterm delivery are associated with the initiation of highly active antiretrovial therapy during pregnancy: a single-center cohort study. J Infect Dis. 2007;196:558–561.
11. Patel K, Shapiro DE, Brogly SB, et al. Prenatal protease inhibitor use and risk of preterm birth among HIV-infected women initiating antiretroviral drugs during pregnancy. J Infect Dis. 2010;201:1035–1044.
12. Powis KM, Kitch D, Ogwu A, et al. Increased risk of preterm delivery among HIV-infected women randomized to protease versus nucleoside reverse transcriptase inhibitor-based ART during pregnancy. J Infect Dis. 2011;204:506–514.
13. Tuomala RE, Shapiro DE, Mofenson LM, et al. Antiretroviral therapy during pregnancy and the risk of an adverse outcome. N Engl J Med. 2002;346:1863–1870.
14. Tuomala RE, Watts DH, Li D, et al. Improved obstetric outcomes and few maternal toxicities are associated with antiretroviral therapy, including highly active antiretroviral therapy during pregnancy. J Acquir Immune Defic Syndr. 2005;38:449–473.
15. Dubicke A, Fransson E, Centini G, et al. Pro-inflammatory and anti-inflammatory cytokines in human preterm and term cervical ripening. J Reprod Immunol. 2008;84:176–185.
16. Duncombe G, Veldhuizen RA, Gratton RJ, et al. IL-6 and TNFalpha across the umbilical circulation in term pregnancies: relationship with labour events. Early Hum Dev. 2010;86:113–117.
17. El-Bastawissi AY, Williams MA, Riley DE, et al. Amniotic fluid interleukin-6 and preterm delivery: a review. Obstet Gynecol. 2000;95:1056–1064.
18. Goldenberg RL, Goepfert AR, Ramsey PS. Biochemical markers for the prediction of preterm birth. Am J Obstet Gynecol. 2005;192(5 suppl):S36–S46.
19. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med. 2000;342:1500–1507.
20. Gomez-Lopez N, Laresgoiti-Servitje E, Olson DM, et al. The role of chemokines in term and premature rupture of the fetal membranes: a review. Biol Reprod. 2010;82:809–814.
21. Gotsch F, Romero R, Erez O, et al. The preterm parturition syndrome and its implications for understanding the biology, risk assessment, diagnosis, treatment and prevention of preterm birth. J Matern Fetal Neonatal Med. 2009;22(suppl 2):5–23.
22. Haddad R, Tromp G, Kuivaniemi H, et al. Human spontaneous labor without histologic chorioamnionitis is characterized by an acute inflammation gene expression signature. Am J Obstet Gynecol. 2006;195:394.e391–e324.
23. Harada M, Osuga Y, Hirota Y, et al. Mechanical stretch stimulates interleukin-8 production in endometrial stromal cells: possible implications in endometrium-related events. J Clin Endocrinol Metab. 2005;90:1144–1148.
24. Hebisch G, Grauaug AA, Neumaier-Wagner PM, et al. The relationship between cervical dilatation, interleukin-6 and interleukin-8 during term labor. Acta Obstet Gynecol Scand. 2001;80:840–848.
25. Kramer MS, Kahn SR, Platt RW, et al. Mid-trimester maternal plasma cytokines and CRP as predictors of spontaneous preterm birth. Cytokine. 2010;49:10–14.
26. Luo G, Abrahams VM, Tadesse S, et al. Progesterone inhibits basal and TNF-alpha-induced apoptosis in fetal membranes: a novel mechanism to explain progesterone-mediated prevention of preterm birth. Reprod Sci. 2010;17:532–539.
27. Lynch AM, Gibbs RS, Murphy JR, et al. Complement activation fragment Bb in early pregnancy and spontaneous preterm birth. Am J Obstet Gynecol. 2008;199:354.e351–e358.
28. Romero R, Espinoza J, Gonçalves LF, et al. The role of inflammation and infection in preterm birth. Semin Reprod Med. 2007;25:21–39.
29. Vaisbuch E, Romero R, Erez O, et al. Activation of the alternative pathway of complement is a feature of pre-term parturition but not of spontaneous labor at term. Am J Reprod Immunol. 2010;63:318–330.
30. Yang Q, El Sayed Y, Shaw GM, et al. Second-trimester serum cytokines in women who develop spontaneous preterm labor at less than 28 weeks' gestation versus term labor. Am J Perinatol. 2009;27:31–36.
31. Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12:1365–1371.
32. Burns DN, Nourjah P, Wright DJ, et al. Changes in immune activation markers during pregnancy and postpartum. J Reprod Immunol. 1999;42:147–165.
33. Ford ES, Greenwald JH, Richterman AG, et al. Traditional risk factors and D-dimer predict incident cardiovascular disease events in chronic HIV infection. AIDS. 2010;24:1509–1517.
34. French MA, King MS, Tschampa JM, et al. Serum immune activation markers are persistently increased in patients with HIV infection after 6 years of antiretroviral therapy despite suppression of viral replication and reconstitution of CD4+ T cells. J Infect Dis. 2009;200:1212–1215.
35. Georgiou HM, Thio YS, Russell C, et al. Association between maternal serum cytokine profiles at 7-10 weeks' gestation and birthweight in small for gestational age infants. Am J Obstet Gynecol. 2011;204:415.e1–415.e12.
36. Giorgi JV, Hultin LE, McKeating JA, et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis. 1999;179:859–870.
37. Iriye BK, Gregory KD, Saade GR, et al. Quality measures in high-risk pregnancies: executive summary of a cooperative workshop of the society for maternal-fetal medicine, national Institute of Child health and human development, and the American College of obstetricians and gynecologists [erratum appears in Am J obstet gynecol. 2018 feb 1; PMID: 29397908]. Am J Obstetrics Gynecol. 2017;217:B2–B25.
38. McComsey GA, Kitch D, Daar ES, et al. Inflammation markers after randomization to abacavir/lamivudine or tenofovir/emtricitabine with efavirenz or atazanavir/ritonavir. AIDS. 2012;26:1371–1385.
39. Neuhaus J, Jacobs DR Jr, Baker JV, et al. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis. 2010;201:1788–1795.
40. Rodger AJ, Fox Z, Lundgren JD, et al. Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection. J Infect Dis. 2009;200:973–983.
41. Sodora DL, Silvestri G. Immune activation and AIDS pathogenesis. AIDS. 2008;22:439–446.
42. Dao CN, Patel P, Overton ET, 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;52:396–405.
43. Smolders J, Peelen E, Thewissen M, et al. Safety and T cell modulating effects of high dose vitamin D3 supplementation in multiple sclerosis. PLoS One. 2010;5:e15235.
44. Correale J, Ysrraelit MC, Gaitan MI. Gender differences in 1,25 dihydroxyvitamin D3 immunomodulatory effects in multiple sclerosis patients and healthy subjects. J Immunol. 2011;185:4948–4958.
45. Wagner CL, McNeil R, Hamilton SA, et al. A randomized trial of vitamin D supplementation in 2 community health center networks in South Carolina. Am J Obstet Gynecol. 2013;208:137.e1–e13.
46. Wagner CL, McNeil RB, Johnson DD, et al. Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis. J Steroid Biochem Mol Biol. 2013;136:313–320.
47. Shibata M, Suzuki A, Sekiya T, et al. High prevalence of hypovitaminosis D in pregnant Japanese women with threatened premature delivery. J Bone Miner Metab. 2011;29:615–620.
48. Møller UK, Streym S, Heickendorff L, et al. Effects of 25OHD concentrations on chances of pregnancy and pregnancy outcomes: a cohort study in healthy Danish women. Eur J Clin Nutr. 2012;66:862–868.
49. Thorp JM, Camargo CA, McGee PL, et al. Vitamin D status and recurrent preterm birth: a nested case-control study in high-risk women. BJOG. 2012;119:1617–1623.
50. Burris HH, Rifas-Shiman SL, Camargo CA Jr, et al. Plasma 25-hydroxyvitamin D during pregnancy and small-for-gestational age in black and white infants. Ann Epidemiol. 2012;22:581–586.
51. Scholl TO, Chen X, Stein P. Maternal vitamin D status and delivery by cesarean. Nutrients. 2012;4:319–330.
52. Roth DE, Morris SK, Zlotkin S, et al. Vitamin D supplementation in pregnancy and lactation and infant growth. N Engl J Med. 2018;379:535–546.
53. Rosen CJ, Abrams SA, Aloia JF, et al. IOM committee members respond to Endocrine Society vitamin D guideline. J Clin Endocrinol Metab. 2012;97:1146–1152.
54. Urrutia RP, Thorp JM. Vitamin D in pregnancy: current concepts. Curr Opin Obstet Gynecol. 2012;24:57–64.
55. Fernandez-Bustamante A, Klawitter J, Wilson P, et al. Early increase in alveolar macrophage prostaglandin 15d-PGJ2 precedes neutrophil recruitment into lungs of cytokine-insufflated rats. Inflammation. 2013;36:1030–1040.
56. Haschke M, Zhang YL, Kahle C, et al. HPLC-atmospheric pressure chemical ionization MS/MS for quantification of 15-F2t-isoprostane in human urine and plasma. Clin Chem. 2007;53:489–497.
57. Klawitter J, Klawitter J, McFann K, et al. Bioactive lipid mediators in polycystic kidney disease. J Lipid Res. 2014;55:1139–1149.
58. Watts DH, Williams PL, Kacanek D, et al. Combination antiretroviral use and preterm birth. J Infect Dis. 2013;207:612–621.
59. Wallenstein MB, Jelliffe-Pawlowski LL, Yang W, et al. Inflammatory biomarkers and spontaneous preterm birth among obese women. J Maternal-Fetal Neonatal Med. 2016;29:3317–3322.
60. Fiore S, Newell ML, Trabattoni D, et al. Antiretroviral therapy-associated modulation of Th1 and Th2 immune responses in HIV-infected pregnant women. J Reprod Immunol. 2006;70:143–150.
61. Cassol E, Malfeld S, Mahasha P, et al. Persistent microbial translocation and immune activation in HIV-1-infected South Africans receiving combination antiretroviral therapy. J Infect Dis. 2010;202:723–733.
62. Redd AD, Dabitao D, Bream JH, et al. Microbial translocation, the innate cytokine response, and HIV-1 disease progression in Africa. Proc Natl Acad Sci U S A. 2009;106:6718–6723.
63. Papp E, Balogun K, Banko N, et al. Low prolactin and high 20-alpha-Hydroxysteroid dehydrogenase levels contribute to lower progesterone levels in HIV-infected pregnant women exposed to protease inhibitor-based combination antiretroviral therapy. J Infect Dis. 2016;213:1532–1540.
64. Mohammadi H, Papp E, Cahill L, et al. HIV antiretroviral exposure in pregnancy induces detrimental placenta vascular changes that are rescued by progesterone supplementation. Sci Rep. 2018;8:6552.
65. Buczynski MW, Dumlao DS, Dennis EA. Thematic Review Series: proteomics. An integrated omics analysis of eicosanoid biology. J Lipid Res. 2009;50:1015–1038.
66. Onodera T, Fukuhara A, Shin J, et al. Eicosapentaenoic acid and 5-HEPE enhance macrophage-mediated Treg induction in mice. Sci Rep. 2017;7:4560.
67. Hollis BW, Johnson D, Hulsey TC, et al. Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res. 2011;26:2341–2357.
68. Liu NQ, Kaplan AT, Lagishetty V, et al. Vitamin D and the regulation of placental inflammation. J Immunol. 2011;186:5968–5974.
69. Pena-Rosas JP, De-Regil LM, Dowswell T, et al. Daily oral iron supplementation during pregnancy. Cochrane Database Syst Rev. 2012;12:CD004736.
70. Shin JS, Choi MY, Longtine MS, et al. Vitamin D effects on pregnancy and the placenta. Placenta. 2010;31:1027–1034.
71. Bodnar LM, Simhan HN, Powers RW, et al. High prevalence of vitamin D insufficiency in black and white pregnant women residing in the northern United States and their neonates. J Nutr. 2007;137:447–452.
72. 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.
73. Allshouse AA, Jessel RH, Heyborne KD. The impact of low-dose aspirin on preterm birth: secondary analysis of a randomized controlled trial. J Perinatol. 2016;36:427–431.
74. Bujold E, Roberge S, Lacasse Y, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol. 2010;116:402–414.
75. Henderson JT, Whitlock EP, O'Connor E, et al. Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2014;160:695–703.
76. Hoffman MK, Goudar SS, Kodkany BS, et al. A description of the methods of the aspirin supplementation for pregnancy indicated risk reduction in nulliparas (ASPIRIN) study. BMC Pregnancy Childbirth. 2017;17:135.
77. Poon LC, Wright D, Rolnik DL, et al. Aspirin for Evidence-Based Preeclampsia Prevention trial: effect of aspirin in prevention of preterm preeclampsia in subgroups of women according to their characteristics and medical and obstetrical history [Erratum appears in Am J Obstet Gynecol. 2018 Feb 1 PMID: 29397907]. Am J Obstet Gynecol. 2017;217:585.e1–585.e5.
78. Roberge S, Nicolaides KH, Demers S, et al. Prevention of perinatal death and adverse perinatal outcome using low-dose aspirin: a meta-analysis. Ultrasound Obstet Gynecol. 2013;41:491–499.
79. Rolnik DL, Wright D, Poon LC, et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med. 2017; 377:613–622.
80. van Vliet EO, Askie LA, Mol BW, et al. Antiplatelet agents and the prevention of spontaneous preterm birth: a systematic review and meta-analysis. Obstet Gynecol. 2017;129:327–336.
81. Wright D, Poon LC, Rolnik DL, et al. Aspirin for Evidence-Based Preeclampsia Prevention trial: influence of compliance on beneficial effect of aspirin in prevention of preterm preeclampsia. Am J Obstet Gynecol. 2017;217:685.e1–685.e5.
Keywords:

human immunodeficiency virus; pregnancy; preterm delivery; vitamin D; eicosanoid; protease inhibitors; inflammation

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