Candice E. Ruck1*
Kinga K. Smolen2,3,4*- 1Department of Experimental Medicine, University of British Columbia, Vancouver, BC, Canada
- 2Department of Pediatrics, Harvard Medical School, Boston, MA, United States
- 3Department of Infectious Disease, Precision Vaccine Program, Boston Children’s Hospital, Boston, MA, United States
- 4Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium
Early life represents a period of profound immunological development and heightened susceptibility to infectious disease. The developmental trajectory over this period is influenced by a number of factors, including gestational age, mode of delivery, mode of feeding, microbiome development, and environmental exposures. There are also several maternal factors that have been shown to have a negative effect on both immune development and clinical outcomes, including maternal infection and inflammation. Studies have associated maternal HIV infections with an increase in infectious morbidity and mortality and decreased growth measures among their HIV-exposed uninfected (HEU) offspring. Among HEU infants, socioeconomic factors, maternal nutrition, maternal viral load, and maternal inflammation have also all been associated with impaired infant immune status and clinical outcomes. However, the mechanisms underlying these observations have not been elucidated and, apart from measures of disease severity, few studies thus far have undertaken in-depth assessments of maternal health status or immune function during gestation and how these influence developmental outcomes in their infants. The lack of a mechanistic understanding of how these gestational influences affect infant outcomes inhibits the ability to design and implement effective interventions. This review describes the current state of research into these mechanisms and highlights areas for future study include; how HIV infection causes the inflammatory trajectory to deviate from normal gestation, the mechanism(s) by which in utero exposure to maternal inflammation influences infant immune development and clinical outcomes, the role of socioeconomic factors as an inducer of maternal stress and inflammation, and maternal nutrition during gestation.
Introduction
Although there is evidence that the underlying trajectory of immune development is fairly resilient (1, 2), studies have also shown that immune development is influenced by a range of factors including gestational age, mode of delivery, mode of feeding, microbiome, and environmental exposure (3–9). Many of these factors have also been associated with impaired clinical outcomes in infants (10–14), including susceptibility to infectious diseases.
Maternal characteristics during gestation can also have a notable effect on infant immune development and clinical outcomes. These include maternal nutrition and microbiome, as well as maternal infection and inflammation (7, 15–18). Maternal HIV in particular has been widely shown to be associated with increased infectious morbidity and mortality, reduced growth parameters, and higher risk of pre-term birth in their HIV-exposed-but-uninfected (HEU) infants (19–22).
There are numerous hypotheses regarding the mechanism(s) underlying the poor outcomes of HEU infants. A definitive consensus remains elusive, and the evidence thus far suggests that the cause is likely multifactorial. Antiretroviral exposure, mode of feeding, a more infectious environment, reduced maternal care, and socioeconomic factors have all been proposed (23). Patterns of altered immune development have also been detected among HEU infants, which may contribute to their increased susceptibility (24). As with the clinical picture, it remains unclear by what mechanism(s) these immune alterations are induced, with in utero HIV exposure, ARV exposure, and the influence of maternal nutrition and microbiome all potential candidates to influence the developing immune system (25, 26). Numerous studies have reported that worse maternal health status, as assessed by viral load or CD4 count, also appears to be associated with poor infant outcomes (27–30). Again, the underlying mechanism(s) are not yet clear. Apart from measures of disease severity, a limited number of studies have undertaken in-depth assessments of maternal health status or immune function and attempted to determine how these influence immune development and infectious outcomes in their infants.
Potential Mechanisms of Maternal Influence on HEU Infant Outcomes
Many mechanisms have been proposed to explain the disparity in clinical outcomes between HEU and HUU infants. Potential factors such as mode of feeding and delivery, while important, are beyond the focus of this review and will be mentioned only briefly here. Several maternal factors have been proposed that may play a role in infant outcomes but have been less well studied. The remainder of this review will focus on these areas.
Maternal HIV Infection
The placenta protects the developing fetus from maternal infections; however, certain viruses possess mechanisms that allow them to evade this protection (31). HIV has been detected in fetal tissues (32–34), confirming that the virus is able to cross the placenta. While this has obvious implications for mother-to-child-transmission (MTCT), in utero HIV exposure presents other potential risks to the developing fetus, including pre-term birth and impaired fetal growth compared to infants born to HIV-negative women (35, 36). Studies have shown that in utero HIV exposure may also have long term effects on the development and function of the infant immune system (24), although the relative contribution of maternal factors has not been elucidated.
Despite the lack of mechanistic explanation, evidence for the effect of in utero HIV exposure on the immune development and function of the infant has been strengthened by numerous studies that have demonstrated a linkage between maternal disease severity, as measured by viral load or CD4 count, and infant outcomes. Reduced maternal CD4 counts have been associated with increased infant mortality (29, 37) and morbidity (27, 28); similarly, high maternal viral load has also been shown to be a significant predictor of infant morbidity and mortality (29). This is not surprising, as where more severe maternal disease will expose the infant to quantitatively higher levels of HIV antigen. There will also be exposure to a maternal immune environment biased towards systemic activation and chronic inflammation. These exposures may, individually or together, influence the development of the infant, resulting in an increased susceptibility to infections in early life.
Infant growth parameters are also influenced by maternal disease severity (38). Low maternal CD4 counts were associated with reduced length-for-age (LAZ) scores over the first two years of life (39). Lower maternal CD4 counts were also associated with reductions in weight-for-age (WAZ) (40, 41), LAZ (41), weight, length, and head circumference measurements (42) as well as increased intrauterine growth restriction (IUGR) (43). Higher maternal cervical HIV RNA (44) and low maternal CD4 counts were associated with increased risk of low birth weight (LBW) (45). A high maternal viral load was significantly associated with infant stunting (46) and lower infant weight (30).
The collective evidence from these studies supports that infants born to mothers with advanced disease are at increased risk of poor outcomes (21, 37, 47–49), although the precise underlying mechanism(s) are not yet known. More severe maternal disease will expose the infant to quantitatively higher levels of viral particles as well as a more activated maternal immune environment biased towards systemic activation and chronic inflammation. These exposures may, individually or combined, exert a deleterious influence on the developing fetus, resulting in poorer infant outcomes.
Maternal Inflammation
Along with hormonal and physiological changes, immunological alterations during pregnancy may increase the risk of adverse infant outcomes (50). In recent years, our knowledge of the maternal immune system during pregnancy has undergone a significant shift. Previously thought to exist primarily in a state of immune suppression to accommodate the semi-allogeneic fetus, our current understanding, while incomplete, now points to a system that is constantly changing according to a predetermined physiological pattern, or ‘pregnancy clock’ (51). Initially, a proinflammatory state is maintained during the first trimester of pregnancy, which is critical for embryo implantation, placentation, and initial fetal growth, followed by transition to an anti-inflammatory state during the rapid fetal growth of the second trimester, and finally a return to a proinflammatory state prior to labor (52).
Despite the natural tendency towards a pro-inflammatory milieu at certain stages of gestation, it has been hypothesized that chronic exposure to low-grade systemic inflammation in fetal and early postnatal life, of the type that is characteristic of HIV infection (53) may result in stunting (54). Maternal HIV infection has been associated with an increased risk of preterm birth, a complication likely related to inflammation at the materno-fetal interface (55, 56). Prendergast et al. further reported strong associations between maternal and infant inflammatory markers at birth, supporting the hypothesis that an increased maternal inflammatory environment contributes to an increase in inflammation in the infant (54). However, these findings have been contradicted by multiple studies that have found that maternal and infant levels of inflammation do not correlate (31, 57, 58) suggesting that the increased levels of inflammatory mediators that have been described in HEU infants may not be solely the result of direct maternal transfer.
Although HIV infection is associated with increased levels of serum inflammatory mediators, it has not conclusively been shown that these cytokines can cross the placenta, making it difficult to accurately gauge their effect on the developing fetus (59). The presence of inflammation in cohorts with controlled maternal viral load suggests that antigenic exposure via placental transfer does not provide an adequate explanation either. Further complicating efforts to determine the impact of maternal inflammation on infant outcomes is the finding reported by multiple studies that maternal HIV infection is associated with lower levels of pro-inflammatory mediators in both mothers and children (60–62), conflicting with studies that have reported increased inflammatory mediators in HEU mothers and infants (58).
Maternal Immunity
Pregnancy involves a tightly regulated immunological trajectory (51) designed to provide adequate immune protection to the mother and fetus while simultaneously maintaining tolerance towards the semi-allogeneic fetus (50). During a healthy pregnancy, the maternal immune system undergoes a series of adaptations in both the adaptive and innate arms (50). Initiated early in pregnancy (63), these adaptations result in a progressive shift from a cell-mediated, pro-inflammatory, Th1-biased profile towards a humoral, anti-inflammatory, Th2-biased profile (64).
Increased maternal immune activation has also been identified as a factor in the association between maternal viral infections and adverse infant outcomes (31). HIV infection and antiretroviral therapy (ART) both impact key immune mechanisms, which may in turn disturb this normal immunological trajectory of pregnancy (65). Maternal HIV infections are commonly associated with increased levels of pro- and anti-inflammatory cytokine levels in cord blood, independent of pathogen transmission (16).
Maternal HIV and ART has been associated with distinct systemic cytokine profiles throughout pregnancy that differ from an HIV- pregnancy profile (65). HIV-exposure has further been shown to affect the maternal/fetal unit, with increased levels of proinflammatory cytokine produced by placenta cells, as well as altered infant immune responses (66). HEU infants have high levels of inflammatory mediators in their cord blood. Further studies are required to address the origin and long-term consequences of prenatal HIV-exposure and subsequent immune activation for infant health.
Maternal Antibodies
Maternal antibodies are a central component of the newborn immunity against pathogens in early life. In healthy pregnancies, antibodies are selectively transferred across the placenta (59), while chronic maternal infections are associated with reduced transfer of IgG across the placenta, presenting a unique ‘disruption model’ (67–70). In HIV positive pregnancies, factors associated with maternal disease progression are associated with poor placental IgG transfer (29, 67, 71–73). The mechanisms underlying this impaired transfer are not fully defined. One hypothesis that has been proposed is that increased levels of maternal antibodies saturate the placental Fc receptor (24). Martinez et al. showed that placental transfer of maternal IgG is a selective process in which a combination of factors, including IgG FcR binding strength, subclass, and glycan profiles, play a role in the selective and differential transfer of maternal antigen-specific IgG across the placenta (67).
The functional potential of antibodies are determined by their glycosylation profile, which defines the Fc receptors that the antibody can bind to (74). Binding to placental Fcγ receptors can predict the transfer of placental IgG transfer efficiency. Altered antibody glycosylation profiles in the context of maternal HIV infection could also be related to the reduced transfer efficiency observed in HEU infants. The occurrence of inflammation due to maternal HIV infection may also negatively influence the passive immune transfer to the fetus (73).
Maternal Microbiome
Over the course of a normal pregnancy, changes naturally occur to the maternal vaginal and gut microbiota (7). The vaginal microbiome becomes less diverse and develops a higher relative abundance of Lactobacillus species (75). There is some evidence of decreased diversity in the gut microbiome as well as pregnancy progresses, along with a shift towards a greater abundance of pro-inflammatory Proteobacteria (76).
Previous studies have shown that HIV infection also alters the composition of the gut microbiome (77). Reported differences include increased diversity and abundance of Prevotella species (77, 78) as well as increased Proteobacteria and decreased Bacteroidetes (53, 78).
Emerging studies have shown that the maternal microbiome plays a major role in the early microbial colonization of the infant as well as in the development of the infant immune system. Factors that disrupt the maternal transfer of microbiota, such as perinatal antibiotics, mode of delivery, and mode of feeding, have been shown to influence the composition of the infant microbiome and have been associated with adverse outcomes later in life (7). A study in Zimbabwe reported an association between gestational maternal gut microbiota and birthweight and neonatal growth (79). In the context of maternal HIV infections, a Haitian study reported that the microbiome of HEU infants was altered compared to that of UE infants (80). However, a study comparing the microbiome of HEU infants across different regions demonstrated that these differences are not universal but rather are complicated by population-dependent differences (81).
Maternal Nutrition
Maternal nutritional status has a strong influence on infant growth and development (82). Fetal growth involves a complex interplay of factors including metabolic and endocrine signaling as well as maternal nutritional and immune status (83). Maternal malnutrition can impair the nutrient stores of the developing fetus, which consequently can inhibit fetal immune function and growth (84). Maternal gestational weight gain and body mass index have been positively associated with infant birth weight (82) while low maternal BMI was associated with an increased risk of low birth weight (85–87). Maternal height has been inversely associated with infant mortality, stunting and underweight in survey data from 54 low- to middle-income countries (88).
Pregnancy increases the need for both absolute calories as well as specific nutrients (89). These increased nutritional requirements are necessary to support the physiological changes that take place during gestation as well as fetal growth and development (90).
HIV infection also increases both energy and micronutrient requirements. Infected individuals often have compromised nutritional status (91) and/or are micronutrient deficient (92, 93). Common HIV-related issues, such as diarrhea, appetite loss, and opportunistic infections, all place an increased burden on available energy stores (84). As such, HIV has long been associated with changes in body mass and composition (84, 94).
Although there is not a great deal of previous literature regarding the specific effect of HIV on nutrition in women, certain sex-specific changes have been identified. HIV infection was associated with a reduction in the fat mass index (FMI) in women, while no difference in FMI was observed between men with and without HIV (94). Further, women suffering from AIDS wasting syndrome experience a disproportionately high decrease in body fat relative to lean body mass compared to men (95).
Both pregnancy and HIV infection increase the risk of anemia. The risk of developing anemia during pregnancy is higher for HIV infected women (96, 97). Maternal anemia has been shown to negatively affect infant outcomes, regardless of infection status. In uninfected mothers, maternal anemia is associated with low birth weight (82) while anemia in HIV-infected mothers was associated with increased risk of PTB and LBW (98) and small-for-gestational-age (SGA) (99).
Taken together, it is apparent that the combined nutritional requirements of pregnancy and HIV can leave HIV-infected mothers at greater risk of malnutrition. This has been borne out by studies in which maternal wasting was shown to be more prevalent in HIV-infected mothers compared to uninfected mothers (90). This compromised nutritional status may also affect the growth and health status of their infants. Reductions in the MUAC of HIV-infected mothers during gestation were associated with reductions in infant WAZ and LAZ through to 6 months of age (100). Similarly, greater maternal weight change during pregnancy was associated with higher LAZ of their HEU infants (101), while lower maternal BMI was associated with lower length and weight gain in their 2 wk old HEU infants (102). Indeed, the use of maternal anthropometry as an indicator of infant outcomes appears to be more applicable in the context of maternal HIV infection than in HIV-negative mothers (103).
Socioeconomic Factors
It is well established that a range of maternal factors influence infant outcomes; developing a comprehensive understanding of these forces needs to include consideration of non-biological factors. Studies into non-biological factors have identified several indicators that are associated with determinants of maternal and infant health. The non-biological maternal factors associated with reduced infant anthropometry are not unique to the HEU population but rather are in line with factors that have previously been identified in UE infants, particularly in lower income countries, such as parental education, income, and number of children within the household (104–106).
Lower educational outcomes have been associated with increased risk of HIV infection among women of childbearing age (107, 108). Maternal education has also been linked to infant health and growth outcomes. Lower maternal education is associated with increased infectious morbidity in infants among both HIV-infected and uninfected women (109) and is an independent predictor of infant stunting, wasting, and underweight measures (46, 110). Reduced maternal education was found to be associated with decreased LAZ and WAZ scores over the first two years of life (39), while maternal illiteracy was identified as a risk factor for reduced linear growth (111). The mechanisms underlying this association have not yet been conclusively established. Higher educational attainment may result in increased knowledge related to hygiene, pre-natal care, childcare, and feeding practices (110). As well, lower education has been associated with reduced knowledge about PMTCT (112) and decreased access to testing (113, 114).
It is possible that education is a surrogate for socioeconomic status, and poverty is the real causative factor (109). Poverty is associated with increased risk of HIV infection (108, 114–116); thus it follows that poverty would also have a role in maternal HIV status. Low socioeconomic status has been associated with poor maternal nutrition and gestational anemia (96, 117, 118) factors that have been linked to worse infant outcomes.
Timing of ART
Given the observed associations between severity of maternal disease and infant health status, it is not surprising that the use of maternal ART has been shown to improve infant outcomes. The benefits of maternal ART use have been well reviewed elsewhere (119–121); this review focuses on the timing with which ART is established relative to pregnancy. There is a conflicting body of literature suggesting that ART initiation can result in HU-equivalent status for the infant if ART was initiated prior to conception or early in pregnancy. Although these findings are still somewhat inconsistent, early studies indicate that this result is at least partly dependent on whether the cohort is located in high-income countries vs low-income countries.
In an Ethiopian study, infants exposed to ART from conception displayed decreased growth compared to those exposed late in pregnancy (122). A Belgian HEU infant cohort reported that initiation of maternal ART before pregnancy reduced the risk of infant infection-related hospitalizations (123). In a Brazilian cohort, although ART use was associated with a high frequency of adverse events in newborns, these were mainly of low severity (124). In contrast, the effect of maternal ART on infant outcomes was not so clear in a South African cohort (125). The mechanisms underlying these distinctions between cohorts are not yet clear and are the basis of ongoing studies. It could be an artifact of differences in study design, or it could be related to population-level differences in health status affecting the study participants.
Future Research Directions and New Technologies
Given the immense influence they have on infant outcomes, maternal factors in the context of HEU infants have been understudied. Gaps in knowledge that should direct future research directions include a more thorough understanding of maternal immunity, particularly the innate arm, and of how immunological markers change across the entire gestational span in both normal and pathological pregnancies (126). Improved standardization of immune measures would also improve the comparability between studies, as well as allowing for a more defined metric to measure the extent of the adverse outcomes in infants. A deeper understanding of the maternal microbiome is also required, and how it affects infant development and outcomes. Further, future studies need to move beyond the observational and begin to attempt to elucidate the underlying mechanisms.
Among the tools that are available to advance these research agendas are the recently developed field of ‘omics technologies. To date, these have primarily been used to map the immune profile of the adults and infants; few comprehensive investigations into maternal profiles exist thus far (127, 128). The systems approach harnesses multiple “omics” technologies and applies computational methodologies to analyze large volumes of data about parameters of various interacting biological systems, can help to address some of these gaps. This pooling of efforts results in a comprehensive, high-resolution picture of a system of interest. The application of these systems has begun to elucidate a number of trajectories in pregnancy, including the characterization of the proteomics, transcriptomics, and metabolomics (51, 129–131). In addition, systems serology is shedding new light on the assessment of antibody function and glycosylation (132).
The main advantages of applying the systems biology approach is the ability to acquire novel insight into immune trajectories and to develop well-defined outcome parameters. Pregnancy has a defined trajectory and complex ontogeny. To best understand the complexity of the trajectory, the timeline needs to be considered. Each trimester, month, and week of pregnancy is marked by rapid development and change. It remains a challenge to determine the optimal degree of granularity required to adequately define this trajectory.
Furthermore, well-defined parameters for outcomes of interest are essential but limited primarily to infant outcome and exclude other factors such as maternal health and long-term health outcomes of the infant. The outcomes of a normal versus impaired immune state in the infant and beyond are nuanced. Defined parameters need to be established for systems biology to assess the presence and clinical relevance of optimal ontogeny and deviation of that trajectory.
Conclusions
Despite the relative lack of attention given to maternal factors, there is sufficient evidence to conclude that maternal HIV infection adversely affects infant outcomes in early life. Among the many reasons for these deleterious outcomes, the focus has largely fallen on feeding practices and ARV exposure. Yet studies have shown that, despite improvements in outcomes in the context of breastfeeding and ARV use, these adverse outcomes persist (133, 134). Further, evidence that the extent of this influence is affected by the severity of maternal disease suggests that the mechanism is at least partly related to in utero exposure, although it remains an open question whether the virus itself or the activated maternal environment is most responsible. Understanding the mechanisms by which in utero HIV exposure affects infant outcomes is the next step towards understanding how best to design effective interventions to improve infant outcomes.
Author Contributions
CR and KS contributed equally to the conceptualized, writing of original draft, and editing of final draft. All authors edited, reviewed, and approved the manuscript prior to submission.
Funding
The work was supported in part by US National Institutes of Health (NIH)/National Institutes of Allergy and Infectious Diseases (NIAID) awards, including Adjuvant Discovery (HHSN272201400052C and 75N93019C00044) and Development (HHSN272201800047C) Program Contracts to Dr. Levy.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Smolen KK, Ruck CE, Fortuno ES, Ho K, Dimitriu P, Mohn WW, et al. Pattern Recognition Receptor-Mediated Cytokine Response in Infants Across 4 Continents. J Allergy Clin Immunol (2014) 133(3):818–26.e4. doi: 10.1016/j.jaci.2013.09.038
2. Olin A, Henckel E, Chen Y, Lakshmikanth T, Pou C, Mikes J, et al. Stereotypic Immune System Development in Newborn Children. Cell (2018) 174(5):1277–1292.e14. doi: 10.1016/j.cell.2018.06.045
3. Bolte EE, Moorshead D, Aagaard KM. Maternal and Early Life Exposures and Their Potential to Influence Development of the Microbiome. Genome Med (2022) 14(1):4–021. doi: 10.1186/s13073-021-01005-7
4. Camacho-Morales A, Caba M, García-Juárez M, Caba-Flores MD, Viveros-Contreras R, Martínez-Valenzuela C. Breastfeeding Contributes to Physiological Immune Programming in the Newborn. Front Pediatr (2021) 9:744104. doi: 10.3389/fped.2021.744104
5. Gaufin T, Tobin NH, Aldrovandi GM. The Importance of the Microbiome in Pediatrics and Pediatric Infectious Diseases. Curr Opin Pediatr (2018) 30(1):117–24. doi: 10.1097/MOP.0000000000000576
6. Yang I, Corwin EJ, Brennan PA, Jordan S, Murphy JR, Dunlop A. The Infant Microbiome: Implications for Infant Health and Neurocognitive Development. Nurs Res (2016) 65(1):76–88. doi: 10.1097/NNR.0000000000000133
7. Mueller NT, Bakacs E, Combellick J, Grigoryan Z, Dominguez-Bello MG. The Infant Microbiome Development: Mom Matters. Trends Mol Med (2015) 21(2):109–17. doi: 10.1016/j.molmed.2014.12.002
8. Cho CE, Norman M. Cesarean Section and Development of the Immune System in the Offspring. Am J Obstet Gynecol (2013) 208(4):249–54. doi: 10.1016/j.ajog.2012.08.009
9. Melville JM, Moss TJ. The Immune Consequences of Preterm Birth. Front Neurosci (2013) 7:79. doi: 10.3389/fnins.2013.00079
10. Turroni F, Milani C, Duranti S, Lugli GA, Bernasconi S, Margolles A, et al. The Infant Gut Microbiome as a Microbial Organ Influencing Host Well-Being. Ital J Pediatr (2020) 46(1):16–020. doi: 10.1186/s13052-020-0781-0
11. Pandolfi E, Gesualdo F, Rizzo C, Carloni E, Villani A, Concato C, et al. Breastfeeding and Respiratory Infections in the First 6 Months of Life: A Case Control Study. Front Pediatr (2019) 7:152. doi: 10.3389/fped.2019.00152
12. Bentley JP, Burgner DP, Shand AW, Bell JC, Miller JE, Nassar N. Gestation at Birth, Mode of Birth, Infant Feeding and Childhood Hospitalization With Infection. Acta Obstet Gynecol Scand (2018) 97(8):988–97. doi: 10.1111/aogs.13371
13. Milani C, Duranti S, Bottacini F, Casey E, Turroni F, Mahony J, et al. The First Microbial Colonizers of the Human Gut: Composition, Activities, and Health Implications of the Infant Gut Microbiota. Microbiol Mol Biol Rev (2017) 81(4):e00036–17. doi: 10.1128/MMBR.00036-17
14. Sevelsted A, Stokholm J, Bønnelykke K, Bisgaard H. Cesarean Section and Chronic Immune Disorders. Pediatrics (2015) 135(1):e92–8. doi: 10.1542/peds.2014-0596
15. Imdad A, Bhutta ZA. Maternal Nutrition and Birth Outcomes: Effect of Balanced Protein-Energy Supplementation. Paediatr Perinat Epidemiol (2012) 26 Suppl 1:178–90. doi: 10.1111/j.1365-3016.2012.01308.x
16. Dauby N, Goetghebuer T, Kollmann TR, Levy J, Marchant A. Uninfected But Not Unaffected: Chronic Maternal Infections During Pregnancy, Fetal Immunity, and Susceptibility to Postnatal Infections. Lancet Infect Dis (2012) 12(4):330–40. doi: 10.1016/S1473-3099(11)70341-3
17. Goldenberg RL, Culhane JF, Johnson DC. Maternal Infection and Adverse Fetal and Neonatal Outcomes. Clin Perinatol (2005) 32(3):523–59. doi: 10.1016/j.clp.2005.04.006
18. Gibbs RS. The Relationship Between Infections and Adverse Pregnancy Outcomes: An Overview. Ann Periodontol (2001) 6(1):153–63. doi: 10.1902/annals.2001.6.1.153
19. Evans C, Jones CE, Prendergast AJ. HIV-Exposed, Uninfected Infants: New Global Challenges in the Era of Paediatric HIV Elimination. Lancet Infect Dis (2016) 16(6):e92–e107. doi: 10.1016/S1473-3099(16)00055-4
20. Slogrove AL, Goetghebuer T, Cotton MF, Singer J, Bettinger JA. Pattern of Infectious Morbidity in HIV-Exposed Uninfected Infants and Children. Front Immunol (2016) 7:164. doi: 10.3389/fimmu.2016.00164
21. Dauby N, Chamekh M, Melin P, Slogrove AL, Goetghebuer T. Increased Risk of Group B Streptococcus Invasive Infection in HIV-Exposed But Uninfected Infants: A Review of the Evidence and Possible Mechanisms. Front Immunol (2016) 7:505. doi: 10.3389/fimmu.2016.00505
22. Brennan AT, Bonawitz R, Gill CJ, Thea DM, Kleinman M, Useem J, et al. A Meta-Analysis Assessing All-Cause Mortality in HIV-Exposed Uninfected Compared With HIV-Unexposed Uninfected Infants and Children. AIDS (2016) 30(15):2351–60. doi: 10.1097/QAD.0000000000001211
23. Filteau S. The HIV-Exposed, Uninfected African Child. Trop Med Int Health (2009) 14(3):276–87. doi: 10.1111/j.1365-3156.2009.02220.x
24. Abu-Raya B, Smolen KK, Willems F, Kollmann TR, Marchant A. Transfer of Maternal Antimicrobial Immunity to HIV-Exposed Uninfected Newborns. Front Immunol (2016) 7:338. doi: 10.3389/fimmu.2016.00338
25. Ruck C, Reikie BA, Marchant A, Kollmann TR, Kakkar F. Linking Susceptibility to Infectious Diseases to Immune System Abnormalities Among HIV-Exposed Uninfected Infants. Front Immunol (2016) 7:310. doi: 10.3389/fimmu.2016.00310
26. Afran L, Garcia Knight M, Nduati E, Urban BC, Heyderman RS, Rowland-Jones SL. HIV-Exposed Uninfected Children: A Growing Population With a Vulnerable Immune System? Clin Exp Immunol (2014) 176(1):11–22. doi: 10.1111/cei.12251
27. Mussi-Pinhata MM, Freimanis L, Yamamoto AY, Korelitz J, Pinto JA, Cruz ML, et al. Infectious Disease Morbidity Among Young HIV-1-Exposed But Uninfected Infants in Latin American and Caribbean Countries: The National Institute of Child Health and Human Development International Site Development Initiative Perinatal Study. Pediatrics (2007) 119(3):e694–704. doi: 10.1542/peds.2006-1856
28. Marquez C, Okiring J, Chamie G, Ruel TD, Achan J, Kakuru A, et al. Increased Morbidity in Early Childhood Among HIV-Exposed Uninfected Children in Uganda is Associated With Breastfeeding Duration. J Trop Pediatr (2014) 60(6):434–41. doi: 10.1093/tropej/fmu045
29. Brahmbhatt H, Kigozi G, Wabwire-Mangen F, Serwadda D, Lutalo T, Nalugoda F, et al. Mortality in HIV-Infected and Uninfected Children of HIV-Infected and Uninfected Mothers in Rural Uganda. J Acquir Immune Defic Syndr (2006) 41(4):504–8. doi: 10.1097/01.qai.0000188122.15493.0a
30. Kuhn L, Kasonde P, Sinkala M, Kankasa C, Semrau K, Scott N, et al. Does Severity of HIV Disease in HIV-Infected Mothers Affect Mortality and Morbidity Among Their Uninfected Infants? Clin Infect Dis (2005) 41(11):1654–61. doi: 10.1086/498029
31. Chudnovets A, Liu J, Narasimhan H, Liu Y, Burd I. Role of Inflammation in Virus Pathogenesis During Pregnancy. J Virol (2020) 95(2):e01381–19. doi: 10.1128/JVI.01381
32. Ikumi NM, Matjila M, Gray CM, Anumba D, Pillay K. Placental Pathology in Women With HIV. Placenta (2021) 115:27–36. doi: 10.1016/j.placenta.2021.09.006
33. Sprecher S, Soumenkoff G, Puissant F, Degueldre M. Vertical Transmission of HIV in 15-Week Fetus. Lancet (1986) 2(8501):288–9. doi: 10.1016/S0140-6736(86)92110-0
34. Backe E, Jimenez E, Unger M, Schafer A, Jauniaux E, Vogel M. Demonstration of HIV-1 Infected Cells in Human Placenta by In Situ Hybridisation and Immunostaining. J Clin Pathol (1992) 45(10):871–4. doi: 10.1136/jcp.45.10.871
35. Mabaya L, Matarira HT, Tanyanyiwa DM, Musarurwa C, Mukwembi J. Growth Trajectories of HIV Exposed and HIV Unexposed Infants. A Prospective Study in Gweru, Zimbabwe. Glob Pediatr Health (2021) 8:2333794X21990338. doi: 10.1177/2333794X21990338
36. Wedi CO, Kirtley S, Hopewell S, Corrigan R, Kennedy SH, Hemelaar J. Perinatal Outcomes Associated With Maternal HIV Infection: A Systematic Review and Meta-Analysis. Lancet HIV (2016) 3(1):e33–48. doi: 10.1016/S2352-3018(15)00207-6
37. Locks LM, Manji KP, Kupka R, Liu E, Kisenge R, McDonald CM, et al. High Burden of Morbidity and Mortality But Not Growth Failure in Infants Exposed to But Uninfected With Human Immunodeficiency Virus in Tanzania. J Pediatr (2017) 180:191–199.e2. doi: 10.1016/j.jpeds.2016.09.040
38. Patel D, Bland R, Coovadia H, Rollins N, Coutsoudis A, Newell ML. Breastfeeding, HIV Status and Weights in South African Children: A Comparison of HIV-Exposed and Unexposed Children. AIDS (2010) 24(3):437–45. doi: 10.1097/QAD.0b013e3283345f91
39. Webb AL, Manji K, Fawzi WW, Villamor E. Time-Independent Maternal and Infant Factors and Time-Dependent Infant Morbidities Including HIV Infection, Contribute to Infant Growth Faltering During the First 2 Years of Life. J Trop Pediatr (2009) 55(2):83–90. doi: 10.1093/tropej/fmn068
40. Morden E, Technau KG, Giddy J, Maxwell N, Keiser O, Davies MA. Growth of HIV-Exposed Uninfected Infants in the First 6 Months of Life in South Africa: The IeDEA-SA Collaboration. PloS One (2016) 11(4):e0151762. doi: 10.1371/journal.pone.0151762
41. Venkatesh KK, Lurie MN, Triche EW, De Bruyn G, Harwell JI, McGarvey ST, et al. Growth of Infants Born to HIV-Infected Women in South Africa According to Maternal and Infant Characteristics. Trop Med Int Health (2010) 15(11):1364–74. doi: 10.1111/j.1365-3156.2010.02634.x
42. Sangeeta T, Anjali M, Silky M, Kosambiya JK, Shah VB. Looking Beyond Prevention of Parent to Child Transmission: Impact of Maternal Factors on Growth of HIV-Exposed Uninfected Infant. Indian J Sex Transm Dis AIDS (2014) 35(2):109–13. doi: 10.4103/0253-7184.142404
43. Cailhol J, Jourdain G, Coeur SL, Traisathit P, Boonrod K, Prommas S, et al. Association of Low CD4 Cell Count and Intrauterine Growth Retardation in Thailand. J Acquir Immune Defic Syndr (2009) 50(4):409–13. doi: 10.1097/QAI.0b013e3181958560
44. Slyker JA, Patterson J, Ambler G, Richardson BA, Maleche-Obimbo E, Bosire R, et al. Correlates and Outcomes of Preterm Birth, Low Birth Weight, and Small for Gestational Age in HIV-Exposed Uninfected Infants. BMC Pregnancy Childbirth (2014) 14:7–2393. doi: 10.1186/1471-2393-14-7
45. Stratton P, Tuomala RE, Abboud R, Rodriguez E, Rich K, Pitt J, et al. Obstetric and Newborn Outcomes in a Cohort of HIV-Infected Pregnant Women: A Report of the Women and Infants Transmission Study. J Acquir Immune Defic Syndr Hum Retrovirol (1999) 20(2):179–86. doi: 10.1097/00042560-199902010-00011
46. McGrath CJ, Nduati R, Richardson BA, Kristal AR, Mbori-Ngacha D, Farquhar C, et al. The Prevalence of Stunting is High in HIV-1-Exposed Uninfected Infants in Kenya. J Nutr (2012) 142(4):757–63. doi: 10.3945/jn.111.148874
47. Shapiro RL, Lockman S. Mortality Among HIV-Exposed Infants: The First and Final Frontier. Clin Infect Dis (2010) 50(3):445–7. doi: 10.1086/649887
48. Shapiro RL, Lockman S, Kim S, Smeaton L, Rahkola JT, Thior I, et al. Infant Morbidity, Mortality, and Breast Milk Immunologic Profiles Among Breast-Feeding HIV-Infected and HIV-Uninfected Women in Botswana. J Infect Dis (2007) 196(4):562–9. doi: 10.1086/519847
49. Slogrove AL, Cotton MF, Esser MM. Severe Infections in HIV-Exposed Uninfected Infants: Clinical Evidence of Immunodeficiency. J Trop Pediatr (2010) 56(2):75–81. doi: 10.1093/tropej/fmp057
50. Abu-Raya B, Michalski C, Sadarangani M, Lavoie PM. Maternal Immunological Adaptation During Normal Pregnancy. Front Immunol (2020) 11:575197. doi: 10.3389/fimmu.2020.575197
51. Aghaeepour N, Lehallier B, Baca Q, Ganio EA, Wong RJ, Ghaemi MS, et al. A Proteomic Clock of Human Pregnancy. Am J Obstet Gynecol (2018) 218(3):347.e1–347.e14. doi: 10.1016/j.ajog.2017.12.208
52. Lin GL, McGinley JP, Drysdale SB, Pollard AJ. Epidemiology and Immune Pathogenesis of Viral Sepsis. Front Immunol (2018) 9:2147. doi: 10.3389/fimmu.2018.02147
53. Vujkovic-Cvijin I, Dunham RM, Iwai S, Maher MC, Albright RG, Broadhurst MJ, et al. Dysbiosis of the Gut Microbiota Is Associated With HIV Disease Progression and Tryptophan Catabolism. Sci Transl Med (2013) 5(193):193ra91. doi: 10.1126/scitranslmed.3006438
54. Prendergast AJ, Rukobo S, Chasekwa B, Mutasa K, Ntozini R, Mbuya MN, et al. Stunting Is Characterized by Chronic Inflammation in Zimbabwean Infants. PloS One (2014) 9(2):e86928. doi: 10.1371/journal.pone.0086928
55. Kemp MW. Preterm Birth, Intrauterine Infection, and Fetal Inflammation. Front Immunol (2014) 5:574. doi: 10.3389/fimmu.2014.00574
56. Lopez M, Figueras F, Coll O, Gonce A, Hernandez S, Lonca M, et al. Inflammatory Markers Related to Microbial Translocation Among HIV-Infected Pregnant Women: A Risk Factor of Preterm Delivery. J Infect Dis (2016) 213(3):343–50. doi: 10.1093/infdis/jiv416
57. Lohman-Payne B, Gabriel B, Park S, Wamalwa D, Maleche-Obimbo E, Farquhar C, et al. HIV-Exposed Uninfected Infants: Elevated Cord Blood Interleukin 8 (IL-8. Is Significantly Associated With Maternal HIV Infection and Systemic IL-8 in a Kenyan Cohort. Clin Transl Med (2018) 7(1):26–018. doi: 10.1186/s40169-018-0206-5
58. Dirajlal-Fargo S, Mussi-Pinhata MM, Weinberg A, Yu Q, Cohen R, Harris DR, et al. HIV-Exposed-Uninfected Infants Have Increased Inflammation and Monocyte Activation. AIDS (2019) 33(5):845–53. doi: 10.1097/QAD.0000000000002128
59. Jennewein MF, Abu-Raya B, Jiang Y, Alter G, Marchant A. Transfer of Maternal Immunity and Programming of the Newborn Immune System. Semin Immunopathol (2017) 39(6):605–13. doi: 10.1007/s00281-017-0653-x
60. Sevenoaks T, Wedderburn CJ, Donald KA, Barnett W, Zar HJ, Stein DJ, et al. Association of Maternal and Infant Inflammation With Neurodevelopment in HIV-Exposed Uninfected Children in a South African Birth Cohort. Brain Behav Immun (2021) 91:65–73. doi: 10.1016/j.bbi.2020.08.021
61. Nhidza AF, Naicker T, Stray-Pedersen B, Gumbo F, Chisango T, Sibanda E, et al. Influence of Maternal Characteristics During Pregnancy on the Infant Early Life Immune Responses in a High HIV Burdened Setting in Harare, Zimbabwe. Afr J Reprod Health (2018) 22(3):43–50. doi: 10.29063/ajrh2018/v22i3.5
62. Maharaj NR, Phulukdaree A, Nagiah S, Ramkaran P, Tiloke C, Chuturgoon AA. Pro-Inflammatory Cytokine Levels in HIV Infected and Uninfected Pregnant Women With and Without Preeclampsia. PloS One (2017) 12(1):e0170063. doi: 10.1371/journal.pone.0170063
63. Raghupathy R, Makhseed M, Azizieh F, Omu A, Gupta M, Farhat R. Cytokine Production by Maternal Lymphocytes During Normal Human Pregnancy and in Unexplained Recurrent Spontaneous Abortion. Hum Reprod (2000) 15(3):713–8. doi: 10.1093/humrep/15.3.713
64. Morelli SS, Mandal M, Goldsmith LT, Kashani BN, Ponzio NM. The Maternal Immune System During Pregnancy and its Influence on Fetal Development. Res Rep Biol (2015) 6:171–19. doi: 10.2147/RRB.S80652
65. Akoto C, Norris SA, Hemelaar J. Maternal HIV Infection is Associated With Distinct Systemic Cytokine Profiles Throughout Pregnancy in South African Women. Sci Rep (2021) 11(1):10079–021. doi: 10.1038/s41598-021-89551-3
66. Pfeifer C, Bunders MJ. Maternal HIV Infection Alters the Immune Balance in the Mother and Fetus; Implications for Pregnancy Outcome and Infant Health. Curr Opin HIV AIDS (2016) 11(2):138–45. doi: 10.1097/COH.0000000000000239
67. Martinez DR, Fong Y, Li SH, Yang F, Jennewein MF, Weiner JA, et al. Fc Characteristics Mediate Selective Placental Transfer of IgG in HIV-Infected Women. Cell (2019) 178(1):190–201.e11. doi: 10.1016/j.cell.2019.05.046
68. Cumberland P, Shulman CE, Maple PA, Bulmer JN, Dorman EK, Kawuondo K, et al. Maternal HIV Infection and Placental Malaria Reduce Transplacental Antibody Transfer and Tetanus Antibody Levels in Newborns in Kenya. J Infect Dis (2007) 196(4):550–7. doi: 10.1086/519845
69. Okoko BJ, Wesuperuma LH, Ota MO, Banya WA, Pinder M, Gomez FS, et al. Influence of Placental Malaria Infection and Maternal Hypergammaglobulinaemia on Materno-Foetal Transfer of Measles and Tetanus Antibodies in a Rural West African Population. J Infect Dis (2001) 184(5):627–32. doi: 10.1086/322808
70. Brair ME, Brabin BJ, Milligan P, Maxwell S, Hart CA. Reduced Transfer of Tetanus Antibodies With Placental Malaria. Lancet (1994) 343(8891):208–9. doi: 10.1016/S0140-6736(94)90991-1
71. Le Doare K, Allen L, Kampmann B, Heath PT, Taylor S, Hesseling AC, et al. Anti-Group B Streptococcus Antibody in Infants Born to Mothers With Human Immunodeficiency Virus (HIV) Infection. Vaccine (2015) 33(5):621–7. doi: 10.1016/j.vaccine.2014.12.025
72. Adler C, Haelterman E, Barlow P, Marchant A, Levy J, Goetghebuer T. Severe Infections in HIV-Exposed Uninfected Infants Born in a European Country. PloS One (2015) 10(8):e0135375. doi: 10.1371/journal.pone.0135375
73. Jones C, Pollock L, Barnett SM, Battersby A, Kampmann B. Specific Antibodies Against Vaccine-Preventable Infections: A Mother-Infant Cohort Study. BMJ Open (2013) 3(4):e002473. doi: 10.1136/bmjopen-2012
74. Bondt A, Rombouts Y, Selman MH, Hensbergen PJ, Reiding KR, Hazes JM, et al. Immunoglobulin G (IgG) Fab Glycosylation Analysis Using a New Mass Spectrometric High-Throughput Profiling Method Reveals Pregnancy-Associated Changes. Mol Cell Proteomics (2014) 13(11):3029–39. doi: 10.1074/mcp.M114.039537
75. Romero R, Hassan SS, Gajer P, Tarca AL, Fadrosh DW, Nikita L, et al. The Composition and Stability of the Vaginal Microbiota of Normal Pregnant Women Is Different From That of Non-Pregnant Women. Microbiome (2014) 2(1):4–2618. doi: 10.1186/2049-2618-2-4
76. Koren O, Goodrich JK, Cullender TC, Spor A, Laitinen K, Bäckhed HK, et al. Host Remodeling of the Gut Microbiome and Metabolic Changes During Pregnancy. Cell (2012) 150(3):470–80. doi: 10.1016/j.cell.2012.07.008
77. Lozupone CA, Li M, Campbell TB, Flores SC, Linderman D, Gebert MJ, et al. Alterations in the Gut Microbiota Associated With HIV-1 Infection. Cell Host Microbe (2013) 14(3):329–39. doi: 10.1016/j.chom.2013.08.006
78. Dillon SM, Lee EJ, Kotter CV, Austin GL, Dong Z, Hecht DK, et al. An Altered Intestinal Mucosal Microbiome in HIV-1 Infection Is Associated With Mucosal and Systemic Immune Activation and Endotoxemia. Mucosal Immunol (2014) 7(4):983–94. doi: 10.1038/mi.2013.116
79. Gough EK, Edens TJ, Geum HM, Baharmand I, Gill SK, Robertson RC, et al. Maternal Fecal Microbiome Predicts Gestational Age, Birth Weight and Neonatal Growth in Rural Zimbabwe. EBioMedicine (2021) 68:103421. doi: 10.1016/j.ebiom.2021.103421
80. Bender JM, Li F, Martelly S, Byrt E, Rouzier V, Leo M, et al. Maternal HIV Infection Influences the Microbiome of HIV-Uninfected Infants. Sci Transl Med (2016) 8(349):349ra100. doi: 10.1126/scitranslmed.aaf5103
81. Amenyogbe N, Kollmann TR, Ben-Othman R. Early-Life Host-Microbiome Interphase: The Key Frontier for Immune Development. Front Pediatr (2017) 5:111. doi: 10.3389/fped.2017.00111
82. Wrottesley SV, Lamper C, Pisa PT. Review of the Importance of Nutrition During the First 1000 Days: Maternal Nutritional Status and Its Associations With Fetal Growth and Birth, Neonatal and Infant Outcomes Among African Women. J Dev Orig Health Dis (2016) 7(2):144–62. doi: 10.1017/S2040174415001439
83. Prendergast AJ, Humphrey JH. The Stunting Syndrome in Developing Countries. Paediatr Int Child Health (2014) 34(4):250–65. doi: 10.1179/2046905514Y.0000000158
84. Piwoz EG, Bentley ME. Women’s Voices, Women’s Choices: The Challenge of Nutrition and HIV/AIDS. J Nutr (2005) 135(4):933–7. doi: 10.1093/jn/135.4.933
85. Gul R, Iqbal S, Anwar Z, Ahdi SG, Ali SH, Pirzada S. Pre-Pregnancy Maternal BMI as Predictor of Neonatal Birth Weight. PloS One (2020) 15(10):e0240748. doi: 10.1371/journal.pone.0240748
86. Zar HJ, Pellowski JA, Cohen S, Barnett W, Vanker A, Koen N, et al. Maternal Health and Birth Outcomes in a South African Birth Cohort Study. PloS One (2019) 14(11):e0222399. doi: 10.1371/journal.pone.0222399
87. Gondwe A, Ashorn P, Ashorn U, Dewey KG, Maleta K, Nkhoma M, et al. Pre-Pregnancy Body Mass Index (BMI) and Maternal Gestational Weight Gain Are Positively Associated With Birth Outcomes in Rural Malawi. PloS One (2018) 13(10):e0206035. doi: 10.1371/journal.pone.0206035
88. Ozaltin E, Hill K, Subramanian SV. Association of Maternal Stature With Offspring Mortality, Underweight, and Stunting in Low- to Middle-Income Countries. JAMA (2010) 303(15):1507–16. doi: 10.1001/jama.2010.450
89. Montgomery KS. Nutrition and HIV-Positive Pregnancy. J Perinat Educ (2003) 12(1):42–7. doi: 10.1891/1058-1243.12.1.42
90. Villamor E, Msamanga G, Spiegelman D, Coley J, Hunter DJ, Peterson KE, et al. HIV Status and Sociodemographic Correlates of Maternal Body Size and Wasting During Pregnancy. Eur J Clin Nutr (2002) 56(5):415–24. doi: 10.1038/sj.ejcn.1601328
91. Gorbach SL, Knox TA, Roubenoff R. Interactions Between Nutrition and Infection With Human Immunodeficiency Virus. Nutr Rev (1993) 51(8):226–34. doi: 10.1111/j.1753-4887.1993.tb03110.x
92. Visser ME, Durao S, Sinclair D, Irlam JH, Siegfried N. Micronutrient Supplementation in Adults With HIV Infection. Cochrane Database Syst Rev (2017) 5(5):CD003650. doi: 10.1002/14651858.CD003650.pub4
93. Drain PK, Kupka R, Mugusi F, Fawzi WW. Micronutrients in HIV-Positive Persons Receiving Highly Active Antiretroviral Therapy. Am J Clin Nutr (2007) 85(2):333–45. doi: 10.1093/ajcn/85.2.333
94. Hegelund MH, Faurholt-Jepsen D, Abdissa A, Yilma D, Andersen Å, Christensen DL, et al. Inflammatory Markers as Correlates of Body Composition and Grip Strength Among Adults With and Without HIV: A Cross-Sectional Study in Ethiopia. Eur J Clin Nutr (2022). doi: 10.1038/s41430-021-01056-4
95. Grinspoon S, Corcoran C, Miller K, Biller BM, Askari H, Wang E, et al. Body Composition and Endocrine Function in Women With Acquired Immunodeficiency Syndrome Wasting. J Clin Endocrinol Metab (1997) 82(5):1332–7. doi: 10.1210/jc.82.5.1332
96. Melku M, Addis Z, Alem M, Enawgaw B. Prevalence and Predictors of Maternal Anemia During Pregnancy in Gondar, Northwest Ethiopia: An Institutional Based Cross-Sectional Study. Anemia (2014) 2014:108593. doi: 10.1155/2014/108593
97. Gangopadhyay R, Karoshi M, Keith L. Anemia and Pregnancy: A Link to Maternal Chronic Diseases. Int J Gynaecol Obstet (2011) 115 Suppl 1:S11–5. doi: 10.1016/S0020-7292(11)60005-2
98. Li HX, Zheng JF, Huang GW, Xiao J, Wang H, Yang M, et al. Prevalence and Associated Risk Factors on Preterm Birth, Low Birth Weight, and Small for Gestational Age Among HIV-Infected Pregnant Women in Hunan Province, 2011-2017. Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi JID (2018) 39(10):1368–74. doi: 10.3760/cma.j.issn.0254-6450.2018.10.015
99. Finkelstein JL, Herman HS, Plenty A, Mehta S, Natureeba P, Clark TD, et al. Anemia and Micronutrient Status During Pregnancy, and Their Associations With Obstetric and Infant Outcomes Among HIV-Infected Ugandan Women Receiving Antiretroviral Therapy. Curr Dev Nutr (2020) 4(5):nzaa075. doi: 10.1093/cdn/nzaa075
100. Wilkinson AL, Pedersen SH, Urassa M, Michael D, Todd J, Kinung’hi S, et al. Associations Between Gestational Anthropometry, Maternal HIV, and Fetal and Early Infancy Growth in a Prospective Rural/Semi-Rural Tanzanian Cohort, 2012-13. BMC Pregnancy Childbirth (2015) 15:277–015. doi: 10.1186/s12884-015-0718-6
101. Lane C, Adair L, Bobrow E, Ndayisaba GF, Asiimwe A, Mugwaneza P. Longitudinal Interrelationship Between HIV Viral Suppression, Maternal Weight Change, Breastfeeding, and Length in HIV-Exposed and Uninfected Infants Participating in the Kabeho Study in Kigali, Rwanda. Ann Epidemiol (2021) 53:1–6.e1. doi: 10.1016/j.annepidem.2020.08.008
102. Widen EM, Bentley ME, Kayira D, Chasela CS, Jamieson DJ, Tembo M, et al. Maternal Weight Loss During Exclusive Breastfeeding Is Associated With Reduced Weight and Length Gain in Daughters of HIV-Infected Malawian Women. J Nutr (2013) 143(7):1168–75. doi: 10.3945/jn.112.171751
103. Petraro P, Madzorera I, Duggan CP, Spiegelman D, Manji K, Kisenge R, et al. Mid-Arm Muscle Area and Anthropometry Predict Low Birth Weight and Poor Pregnancy Outcomes in Tanzanian Women With HIV. BMC Pregnancy Childbirth (2018) 18(1):500–018. doi: 10.1186/s12884-018-2136-z
104. Rahman A, Chowdhury S. Determinants of Chronic Malnutrition Among Preschool Children in Bangladesh. J Biosoc Sci (2007) 39(2):161–73. doi: 10.1017/S0021932006001295
105. König Walles J, Balcha TT, Winqvist N, Björkman P. Growth Pattern in Ethiopian Infants - The Impact of Exposure to Maternal HIV Infection in Relation to Socio-Economic Factors. Glob Health Action (2017) 10(1):1296726. doi: 10.1080/16549716.2017.1296726
106. Muhangi L, Lule SA, Mpairwe H, Ndibazza J, Kizza M, Nampijja M, et al. Maternal HIV Infection and Other Factors Associated With Growth Outcomes of HIV-Uninfected Infants in Entebbe, Uganda. Public Health Nutr (2013) 16(9):1548–57. doi: 10.1017/S1368980013000499
107. Bunyasi EW, Coetzee DJ. Relationship Between Socioeconomic Status and HIV Infection: Findings From a Survey in the Free State and Western Cape Provinces of South Africa. BMJ Open (2017) 7(11):e016232–2017. doi: 10.1136/bmjopen-2017-016232
108. Ekholuenetale M, Onuoha H, Ekholuenetale CE, Barrow A, Nzoputam CI. Socioeconomic Inequalities in Human Immunodeficiency Virus (HIV) Sero-Prevalence Among Women in Namibia: Further Analysis of Population-Based Data. Int J Environ Res Public Health (2021) 18(17):9397. doi: 10.3390/ijerph18179397
109. Moukarzel S, Ozias M, Kerling E, Christifano D, Wick J, Colombo J, et al. Maternal Vitamin D Status and Infant Infection. Nutrients (2018) 10(2):111. doi: 10.3390/nu10020111
110. McDonald CM, Kupka R, Manji KP, Okuma J, Bosch RJ, Aboud S, et al. Predictors of Stunting, Wasting and Underweight Among Tanzanian Children Born to HIV-Infected Women. Eur J Clin Nutr (2012) 66(11):1265–76. doi: 10.1038/ejcn.2012.136
111. Villamor E, Fataki MR, Bosch RJ, Mbise RL, Fawzi WW. Human Immunodeficiency Virus Infection, Diarrheal Disease and Sociodemographic Predictors of Child Growth. Acta Paediatr (2004) 93(3):372–9. doi: 10.1111/j.1651-2227.2004.tb02964.x
112. Alemu YM, Habtewold TD, Alemu SM. Mother’s Knowledge on Prevention of Mother-to-Child Transmission of HIV, Ethiopia: A Cross Sectional Study. PloS One (2018) 13(9):e0203043. doi: 10.1371/journal.pone.0203043
113. Jooste S, Mabaso M, Taylor M, North A, Shean Y, Simbayi LC. Socio-Economic Differences in the Uptake of HIV Testing and Associated Factors in South Africa. BMC Public Health (2021) 21(1):1591–021. doi: 10.1186/s12889-021-11583-1
114. Wabiri N, Taffa N. Socio-Economic Inequality and HIV in South Africa. BMC Public Health (2013) 13:1037–2458. doi: 10.1186/1471-2458-13-1037
115. Pons-Duran C, González R, Quintó L, Munguambe K, Tallada J, Naniche D, et al. Association Between HIV Infection and Socio-Economic Status: Evidence From a Semirural Area of Southern Mozambique. Trop Med Int Health (2016) 21(12):1513–21. doi: 10.1111/tmi.12789
116. Fawzi MC, Lambert W, Boehm F, Finkelstein JL, Singler JM, Léandre F, et al. Economic Risk Factors for HIV Infection Among Women in Rural Haiti: Implications for HIV Prevention Policies and Programs in Resource-Poor Settings. J Womens Health (Larchmt) (2010) 19(5):885–92. doi: 10.1089/jwh.2008.1334
117. Bekele A, Tilahun M, Mekuria A. Prevalence of Anemia and Its Associated Factors Among Pregnant Women Attending Antenatal Care in Health Institutions of Arba Minch Town, Gamo Gofa Zone, Ethiopia: A Cross-Sectional Study. Anemia (2016) 2016:1073192. doi: 10.1155/2016/1073192
118. Kare AP, Gujo AB. Anemia Among Pregnant Women Attending Ante Natal Care Clinic in Adare General Hospital, Southern Ethiopia: Prevalence and Associated Factors. Health Serv Insights (2021) 14:11786329211036303. doi: 10.1177/11786329211036303
119. Selph SS, Bougatsos C, Dana T, Grusing S, Chou R. Screening for HIV Infection in Pregnant Women: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA (2019) 321(23):2349–60. doi: 10.1001/jama.2019.2593
120. Fowler MG, Flynn P, Aizire J. What Is New in Perinatal HIV Prevention? Curr Opin Pediatr (2018) 30(1):144–51. doi: 10.1097/MOP.0000000000000579
121. Bailey H, Zash R, Rasi V, Thorne C. HIV Treatment in Pregnancy. Lancet HIV (2018) 5(8):e457–67. doi: 10.1016/S2352-3018(18)30059-6
122. Ejigu Y, Magnus JH, Sundby J, Magnus MC. Differences in Growth of HIV-Exposed Uninfected Infants in Ethiopia According to Timing of In-Utero Antiretroviral Therapy Exposure. Pediatr Infect Dis J (2020) 39(8):730–6. doi: 10.1097/INF.0000000000002678
123. Goetghebuer T, Smolen KK, Adler C, Das J, McBride T, Smits G, et al. Initiation of Antiretroviral Therapy Before Pregnancy Reduces the Risk of Infection-Related Hospitalization in Human Immunodeficiency Virus-Exposed Uninfected Infants Born in a High-Income Country. Clin Infect Dis (2019) 68(7):1193–203. doi: 10.1093/cid/ciy673
124. Delicio AM, Lajos GJ, Amaral E, Cavichiolli F, Polydoro M, Milanez H. Adverse Effects in Children Exposed to Maternal HIV and Antiretroviral Therapy During Pregnancy in Brazil: A Cohort Study. Reprod Health (2018) 15(1):76–018. doi: 10.1186/s12978-018-0513-8
125. Slogrove AL, Powis KM, Cotton MF. Human Immunodeficiency Virus-Exposed Uninfected Infants: Surviving and Thriving or Overlooked by Success? Clin Infect Dis (2019) 68(12):2156–8. doi: 10.1093/cid/ciy1056
126. PrabhuDas M, Bonney E, Caron K, Dey S, Erlebacher A, Fazleabas A, et al. Immune Mechanisms at the Maternal-Fetal Interface: Perspectives and Challenges. Nat Immunol (2015) 16(4):328–34. doi: 10.1038/ni.3131
127. Ghaemi MS, DiGiulio DB, Contrepois K, Callahan B, Ngo TTM, Lee-McMullen B, et al. Multiomics Modeling of the Immunome, Transcriptome, Microbiome, Proteome and Metabolome Adaptations During Human Pregnancy. Bioinformatics (2019) 35(1):95–103. doi: 10.1093/bioinformatics/bty537
128. Tarca AL, Pataki BÁ, Romero R, Sirota M, Guan Y, Kutum R, et al. Crowdsourcing Assessment of Maternal Blood Multi-Omics for Predicting Gestational Age and Preterm Birth. Cell Rep Med (2021) 2(6):100323. doi: 10.1016/j.xcrm.2021.100323
129. Vora NL, Hui L. Next-Generation Sequencing and Prenatal ’Omics: Advanced Diagnostics and New Insights Into Human Development. Genet Med (2018) 20(8):791–9. doi: 10.1038/s41436-018-0087-4
130. Benny PA, Alakwaa FM, Schlueter RJ, Lassiter CB, Garmire LX. A Review of Omics Approaches to Study Preeclampsia. Placenta (2020) 92:17–27. doi: 10.1016/j.placenta.2020.01.008
131. Espinosa C, Becker M, Marić I, Wong RJ, Shaw GM, Gaudilliere B, et al. Data-Driven Modeling of Pregnancy-Related Complications. Trends Mol Med (2021) 27(8):762–76. doi: 10.1016/j.molmed.2021.01.007
132. Jennewein MF, Goldfarb I, Dolatshahi S, Cosgrove C, Noelette FJ, Krykbaeva M, et al. Fc Glycan-Mediated Regulation of Placental Antibody Transfer. Cell (2019) 178(1):202–215.e14. doi: 10.1016/j.cell.2019.05.044
133. le Roux SM, Abrams EJ, Donald KA, Brittain K, Phillips TK, Nguyen KK, et al. Growth Trajectories of Breastfed HIV-Exposed Uninfected and HIV-Unexposed Children Under Conditions of Universal Maternal Antiretroviral Therapy: A Prospective Study. Lancet Child Adolesc Health (2019) 3(4):234–44. doi: 10.1016/S2352-4642(19)30007-0
134. le Roux SM, Abrams EJ, Donald KA, Brittain K, Phillips TK, Zerbe A, et al. Infectious Morbidity of Breastfed, HIV-Exposed Uninfected Infants Under Conditions of Universal Antiretroviral Therapy in South Africa: A Prospective Cohort Study. Lancet Child Adolesc Health (2020) 4(3):220–31. doi: 10.1016/S2352-4642(19)30375-X
Keywords: maternal HIV, maternal inflammation, HIV-exposed uninfected (HEU), infant development, pregnancy and maternal infection
Citation: Ruck CE and Smolen KK (2022) Effect of Maternal HIV Infection on Infant Development and Outcomes. Front.Virol. 2:885246. doi: 10.3389/fviro.2022.885246
Received: 27 February 2022; Accepted: 28 March 2022;
Published: 23 May 2022.
Edited by:
Caroline T Tiemessen, National Institute of Communicable Diseases (NICD), South AfricaReviewed by:
Melinda Shelley Suchard, National Institute of Communicable Diseases (NICD), South AfricaCopyright © 2022 Ruck and Smolen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Candice E. Ruck, candice.ruck@gmail.com; Kinga K. Smolen, kinga.smolen@childrens.harvard.edu