Inflammation and cytomegalovirus viremia during pregnancy drive sex-differentiated differences in mortality and immune development in HIV-exposed infants.

Children who are HIV-exposed but uninfected have increased infectious mortality compared to HIV-unexposed children, raising the possibility of immune abnormalities following exposure to maternal viraemia, immune dysfunction, and co-infections during pregnancy. In a secondary analysis of the SHINE trial in rural Zimbabwe we explored biological pathways underlying infant mortality, and maternal factors shaping immune development in HIV-exposed uninfected infants. Maternal inflammation and cytomegalovirus viraemia were independently associated with infant deaths: mortality doubled for each log10 rise in maternal C-reactive protein (adjusted hazard ratio (aHR) 2.09; 95% CI 1.33-3.27), and increased 1.6-fold for each log10 rise in maternal cytomegalovirus viral load (aHR 1.62; 95% CI 1.11-2.36). In girls, mortality was more strongly associated with maternal C-reactive protein than cytomegalovirus; in boys, mortality was more strongly associated with cytomegalovirus than C-reactive protein. At age one month, HIV-exposed uninfected infants had a distinct immune milieu, characterised by raised soluble CD14 and an altered CD8 + T-cell compartment. Alterations in immunophenotype and systemic inflammation were generally greater in boys than girls. Collectively, these findings show how the pregnancy immune environment in women with HIV underlies mortality and immune development in their offspring in a sex-differentiated manner, and highlights potential new intervention strategies to transform outcomes of HIV-exposed children. ClinicalTrials.gov/NCT01824940.

Inflammation and epithelial repair predict mortality, hospital readmission, and growth recovery in complicated severe acute malnutrition.

Severe acute malnutrition (SAM) is the most high-risk form of undernutrition, particularly when children require hospitalization for complications. Complicated SAM is a multisystem disease with high inpatient and postdischarge mortality, especially in children with comorbidities such as HIV; however, the underlying pathogenesis of complicated SAM is poorly understood. Targeted multiplex biomarker analysis in children hospitalized with SAM (n = 264) was conducted on plasma samples, and inflammatory markers were assessed on stool samples taken at recruitment, discharge, and 12 to 24 and 48 weeks after discharge from three hospitals in Zimbabwe and Zambia. Compared with adequately nourished controls (n = 173), we found that at baseline, complicated SAM was characterized by systemic, endothelial, and intestinal inflammation, which was exacerbated by HIV infection. This persisted over 48 weeks despite nutritional recovery and was associated with children's outcomes. Baseline plasma concentrations of vascular endothelial growth factor, glucagon-like peptide-2, and intestinal fatty acid-binding protein were independently associated with lower mortality or hospital readmission over the following 48 weeks. Following principal components analysis of baseline biomarkers, higher scores of a component representing growth factors was associated with greater weight-for-height z score recovery and lower mortality or hospital readmission over the 48 weeks. Conversely, components representing higher gut and systemic inflammation were associated with higher mortality or hospital readmission. These findings highlight the interplay between inflammation, which damages tissues, and growth factors, which mediate endothelial and epithelial regeneration, and support further studies investigating interventions to reduce inflammation and promote epithelial repair as an approach to reducing mortality and improving nutritional recovery.

Severe acute malnutrition promotes bacterial binding over proinflammatory cytokine secretion by circulating innate immune cells.

Children with severe acute malnutrition (SAM) have high infectious mortality and morbidity, implicating defects in their immune defenses. We hypothesized that circulating innate immune cells from children (0 to 59 months) hospitalized with SAM in Zambia and Zimbabwe (n = 141) have distinct capacity to respond to bacteria relative to adequately nourished healthy controls (n = 92). SAM inpatients had higher neutrophil and monocyte Escherichia coli binding capacity but lower monocyte activation and proinflammatory mediator secretion in response to lipopolysaccharide or heat-killed Salmonella typhimurium than controls. Among SAM cases, wasting severity was negatively associated with cytokine secretion, children with HIV had lower monocyte activation, and the youngest children released the least myeloperoxidase upon stimulation. Inpatient bacterial binding capacity and monocyte activation were associated with higher odds of persistent SAM at discharge, a risk factor for subsequent mortality. Thus, SAM shifts innate immune cell function, favoring bacterial containment over proinflammatory activation, which may contribute to health deficits after discharge.

Risk factors for inpatient mortality among children with severe acute malnutrition in Zimbabwe and Zambia.

BACKGROUND/OBJECTIVES: Malnutrition underlies 45% of deaths in children under-5 years annually. Children hospitalised with complicated severe acute malnutrition (SAM) have unacceptably high mortality. We aimed to identify variables from early hospital admission (baseline factors) independently associated with inpatient mortality in this cohort to identify those most at risk. SUBJECTS/METHODS: Observational study of 745 children aged 0-59 months admitted with complicated SAM at three hospitals in Zimbabwe/Zambia. Children underwent anthropometry and clinical assessment by a study physician within 72 h of enrolment, and caregivers provided sociodemographic data. Children were followed-up daily until discharge/death. A multivariable survival analysis identified the baseline factors independently associated with mortality. RESULTS: 70/745 (9.4%) children died in hospital. Age between 6-23 months [aHR 6.53, 95%CI 2.24-19.02], higher mid-upper arm circumference [aHR 0.73, 95%CI 0.59-0.89], presence of oedema [aHR 2.22, 95%CI 1.23-4.05], shock [aHR 8.18, 95%CI 3.79-17.65], sepsis [aHR 3.13, 95%CI 1.44-6.80], persistent diarrhoea [aHR 2.27, 95%CI 1.18-4.37], lack of a toilet at home [aHR 4.35, 95%CI 1.65-11.47], and recruitment at one Harare site [aHR 0.38, 95%CI 0.18-0.83] were all independently associated with inpatient mortality. Oedematous children had a significantly higher birthweight [2987 g vs 2757 g, p < 0.001] than those without oedema; higher birthweight was weakly associated with mortality [aHR 1.50 95%CI 0.97-2.31]. CONCLUSIONS: Children with oedema, low MUAC, baseline infections, shock and lack of home sanitation had a significantly increased risk of inpatient mortality following hospitalisation for complicated SAM. Children with high-risk features may require additional care. A better understanding of the pathophysiology of SAM is needed to identify adjunctive interventions.

Malnourished Microbes: Host-Microbiome Interactions in Child Undernutrition.

Childhood undernutrition is a major global health burden that is only partially resolved by nutritional interventions. Both chronic and acute forms of child undernutrition are characterized by derangements in multiple biological systems including metabolism, immunity, and endocrine systems. A growing body of evidence supports a role of the gut microbiome in mediating these pathways influencing early life growth. Observational studies report alterations in the gut microbiome of undernourished children, while preclinical studies suggest that this can trigger intestinal enteropathy, alter host metabolism, and disrupt immune-mediated resistance against enteropathogens, each of which contribute to poor early life growth. Here, we compile evidence from preclinical and clinical studies and describe the emerging pathophysiological pathways by which the early life gut microbiome influences host metabolism, immunity, intestinal function, endocrine regulation, and other pathways contributing to child undernutrition. We discuss emerging microbiome-directed therapies and consider future research directions to identify and target microbiome-sensitive pathways in child undernutrition.

Inflammation: the driver of poor outcomes among children with severe acute malnutrition?

Severe acute malnutrition (SAM) is the most life-threatening form of undernutrition and underlies at least 10% of all deaths among children younger than 5 years in low-income countries. SAM is a complex, multisystem disease, with physiological perturbations observed in conjunction with the loss of lean mass, including structural and functional changes in many organ systems. Despite the high mortality burden, predominantly due to infections, the underlying pathogenic pathways remain poorly understood. Intestinal and systemic inflammation is heightened in children with SAM. Chronic inflammation and its consequent immunomodulation may explain the increased morbidity and mortality from infections in children with SAM, both during hospitalization and in the longer term after discharge. Recognition of the role of inflammation in SAM is critical in considering new therapeutic targets in this disease, which has not seen a transformational approach to treatment for several decades. This review highlights the central role of inflammation in the wide-ranging pathophysiology of SAM, as well as identifying potential interventions that have biological plausibility based on evidence from other inflammatory syndromes.

Stunting Status and Exposure to Infection and Inflammation in Early Life Shape Antibacterial Immune Cell Function Among Zimbabwean Children.

Background: Children who are stunted (length-for-age Z-score<-2) are at greater risk of infectious morbidity and mortality. Previous studies suggest that stunted children have elevated inflammatory biomarkers, but no studies have characterised their capacity to respond to new infections (i.e., their immune function). We hypothesised that antibacterial immune function would differ between stunted and non-stunted children and relate to their health and environment during early life. Methods: We enrolled a cross-sectional cohort of 113 HIV-negative children nested within a longitudinal cluster-randomised controlled trial of household-level infant and young child feeding (IYCF) and water, sanitation and hygiene (WASH) interventions in rural Zimbabwe (SHINE; Clinical trials registration: NCT01824940). Venous blood was collected at 18 months of age and cultured for 24 h without antigen or with bacterial antigens: heat-killed Salmonella typhimurium (HKST) or Escherichia coli lipopolysaccharide (LPS). TNFα, IL-6, IL-8, IL-12p70, hepcidin, soluble (s)CD163, myeloperoxidase (MPO) and IFNß were quantified in culture supernatants by ELISA to determine antigen-specific immune function. The effect of stunting status and early-life exposures (anthropometry, inflammation at 18 months, maternal health during pregnancy, household WASH) on immune function was tested in logit and censored log-normal (tobit) regression models. Results: Children who were stunted (n = 44) had higher proportions (86.4% vs. 65.2%; 88.6% vs. 73.4%) and concentrations of LPS-specific IL-6 (geometric mean difference (95% CI): 3.46 pg/mL (1.09, 10.80), p = 0.035) and IL-8 (3.52 pg/mL (1.20, 10.38), p = 0.022) than non-stunted children (n = 69). Bacterial antigen-specific pro-inflammatory cytokine concentrations were associated with biomarkers of child enteropathy at 18 months and biomarkers of systemic inflammation and enteropathy in their mothers during pregnancy. Children exposed to the WASH intervention (n = 33) produced higher LPS- (GMD (95% CI): 10.48 pg/mL (1.84, 60.31), p = 0.008) and HKST-specific MPO (5.10 pg/mL (1.77, 14.88), p = 0.003) than children in the no WASH group (n = 80). There was no difference in antigen-specific immune function between the IYCF (n = 55) and no IYCF groups (n = 58). Conclusions: Antibacterial immune function among 18-month-old children in a low-income setting was shaped by their stunting status and prior exposure to maternal inflammation and household WASH. Heterogeneity in immune function due to adverse exposures in early life could plausibly contribute to infection susceptibility.

Recovery of children following hospitalisation for complicated severe acute malnutrition.

Nutritional recovery and hospital readmission following inpatient management of complicated severe acute malnutrition (SAM) are poorly characterised. We aimed to ascertain patterns and factors associated with hospital readmission, nutritional recovery and morbidity, in children discharged from hospital following management of complicated SAM in Zambia and Zimbabwe over 52-weeks posthospitalization. Multivariable Fine-Gray subdistribution hazard models, with death and loss to follow-up as competing risks, were used to identify factors associated with hospital readmission; negative binomial regression to assess time to hospitalisation and ordinal logistic regression to model factors associated with nutritional recovery. A total of 649 children (53% male, median age 18.2 months) were discharged to continue community nutritional rehabilitation. All-cause hospital readmission was 15.4% (95% CI 12.7, 18.6) over 52 weeks. Independent risk factors for time to readmission were cerebral palsy (adjusted subhazard ratio (aSHR): 2.96, 95% CI 1.56, 5.61) and nonoedematous SAM (aSHR: 1.64, 95%CI 1.03, 2.64). Unit increases in height-for-age Z-score (HAZ) (aSHR: 0.82, 95% CI 0.71, 0.95) and enrolment in Zambia (aSHR: 0.52, 95% CI 0.28, 0.97) were associated with reduced subhazard of time to readmission. Young age, SAM at discharge, nonoedematous SAM and cerebral palsy were associated with poor nutritional recovery throughout follow-up. Collectively, nonoedematous SAM, ongoing SAM at discharge, cerebral palsy and low HAZ are independent risk factors for readmission and poor nutritional recovery following complicated SAM. Children with these high-risk features should be prioritised for additional convalescent care to improve long-term outcomes.

Understanding the role of the gut in undernutrition: what can technology tell us?

Gut function remains largely underinvestigated in undernutrition, despite its critical role in essential nutrient digestion, absorption and assimilation. In areas of high enteropathogen burden, alterations in gut barrier function and subsequent inflammatory effects are observable but remain poorly characterised. Environmental enteropathy (EE)-a condition that affects both gut morphology and function and is characterised by blunted villi, inflammation and increased permeability-is thought to play a role in impaired linear growth (stunting) and severe acute malnutrition. However, the lack of tools to quantitatively characterise gut functional capacity has hampered both our understanding of gut pathogenesis in undernutrition and evaluation of gut-targeted therapies to accelerate nutritional recovery. Here we survey the technology landscape for potential solutions to improve assessment of gut function, focussing on devices that could be deployed at point-of-care in low-income and middle-income countries (LMICs). We assess the potential for technological innovation to assess gut morphology, function, barrier integrity and immune response in undernutrition, and highlight the approaches that are currently most suitable for deployment and development. This article focuses on EE and undernutrition in LMICs, but many of these technologies may also become useful in monitoring of other gut pathologies.

Determinants of Urogenital Schistosomiasis Among Pregnant Women and its Association With Pregnancy Outcomes, Neonatal Deaths, and Child Growth.

BACKGROUND: Schistosoma haematobium is a parasitic helminth that causes urogenital pathology. The impact of urogenital schistosomiasis during pregnancy on birth outcomes and child growth is poorly understood. METHODS: Risk factors for urogenital schistosomiasis were characterized among 4437 pregnant women enrolled in a cluster-randomized community-based trial in rural Zimbabwe. Infection was defined via urine microscopy (≥1 S. haematobium egg) and urinalysis (hematuria). Associations between infection and pregnancy outcomes were assessed in case-control analyses using conditional logistic regression. The association of maternal infection with birthweight and length-for-age Z scores (LAZ) at 1 and 18 months of age were assessed using generalized estimating equations. RESULTS: Urogenital schistosomiasis (egg positive and/or hematuria positive) was detected in 26.8% of pregnant women. Risk factors significantly associated with infection were maternal age, education, marital status, and religion; household drinking water source and latrine; study region; and season. Urogenital schistosomiasis was not significantly associated with adverse pregnancy outcomes (miscarriage, stillbirth, preterm, and small-for-gestational age), birthweight, neonatal death, or LAZ. CONCLUSIONS: Including pregnant women in antihelminthic treatment programs would benefit a large number of women in rural Zimbabwe. However, clearance of the low-intensity infections that predominate in this context is unlikely to have additive benefits for pregnancy outcomes or child growth. CLINICAL TRIALS REGISTRATION: NCT01824940.

Can breastfeeding protect against antimicrobial resistance?

BACKGROUND: The proportion of infections among young children that are antimicrobial-resistant is increasing across the globe. Newborns may be colonized with enteric antimicrobial-resistant pathogens early in life, which is a risk factor for infection-related morbidity and mortality. Breastfeeding is actively promoted worldwide for its beneficial impacts on newborn health and gut health. However, the role of breastfeeding and human milk components in mitigating young children's carriage of antimicrobial-resistant pathogens and antibiotic resistance genes has not been comprehensively explored. MAIN BODY: Here, we review how the act of breastfeeding, early breastfeeding, and/or human milk components, such as the milk microbiota, secretory IgA, human milk oligosaccharides, antimicrobial peptides, and microRNA -bearing extracellular vesicles, could play a role in preventing the establishment of antimicrobial-resistant pathogens in young children's developing gut microbiomes. We describe findings from recent human studies that support this concept. CONCLUSION: Given the projected rise in global morbidity and mortality that will stem from antimicrobial-resistant infections, identifying behavioral or nutritional interventions that could decrease children's susceptibility to colonization with antimicrobial-resistant pathogens may be one strategy for protecting their health. We suggest that breastfeeding and human milk supplements deserve greater attention as potential preventive measures in the global effort to combat antimicrobial resistance, particularly in low- and middle-income settings.

Strain-level analysis of gut-resident pro-inflammatory viridans group Streptococci suppressed by long-term cotrimoxazole prophylaxis among HIV-positive children in Zimbabwe.

Antimicrobials have become a mainstay of healthcare in the past century due to their activity against pathogens. More recently, it has become clear that they can also affect health via their impact on the microbiota and inflammation. This may explain some of their clinical benefits despite global increases in antimicrobial resistance (AMR) and reduced antimicrobial effectiveness. We showed in a randomized controlled trial of stopping versus continuing cotrimoxazole prophylaxis among HIV-positive Zimbabwean children taking antiretroviral therapy (ART), that continuation of cotrimoxazole persistently suppressed gut-resident viridans group streptococcal species (VGS) that were associated with intestinal inflammation. In this addendum, we provide a broader overview of how antibiotics can shape the microbiota and use high read-depth whole metagenome sequencing data from our published study to investigate whether (i) the impact of cotrimoxazole on gut VGS and (ii) VGS associated inflammation, is attributable to strain-level variability. We focus on S. salivarius, the VGS species that was most prevalent in the cohort and for which there was sufficient genome coverage to differentiate strains. We demonstrate that suppression of S. salivarius by cotrimoxazole is not strain specific, nor did stool concentration of the pro-inflammatory mediator myeloperoxidase vary by S. salivarius strain. We also show that gut-resident S. salivarius strains present in this study population are distinct from common oral strains. This is the first analysis of how cotrimoxazole prophylaxis used according to international treatment guidelines for children living with HIV influences the gut microbiome at the strain-level. We also provide a detailed review of the literature on the mechanisms by which suppression of VGS may act synergistically with cotrimoxazole's anti-inflammatory effects to reduce gut inflammation. A greater understanding of the sub-clinical effects of antibiotics offers new insights into their responsible clinical use.

Current Understanding of Innate Immune Cell Dysfunction in Childhood Undernutrition.

Undernutrition affects millions of children in low- and middle-income countries (LMIC) and underlies almost half of all deaths among children under 5 years old. The growth deficits that characterize childhood undernutrition (stunting and wasting) result from simultaneous underlying defects in multiple physiological processes, and current treatment regimens do not completely normalize these pathways. Most deaths among undernourished children are due to infections, indicating that their anti-pathogen immune responses are impaired. Defects in the body's first-line-of-defense against pathogens, the innate immune system, is a plausible yet understudied pathway that could contribute to this increased infection risk. In this review, we discuss the evidence for innate immune cell dysfunction from cohort studies of childhood undernutrition in LMIC, highlighting knowledge gaps in almost all innate immune cell types. We supplement these gaps with insights from relevant experimental models and make recommendations for how human and animal studies could be improved. A better understanding of innate immune function could inform future tractable immune-targeted interventions for childhood undernutrition to reduce mortality and improve long-term health, growth and development.

Cotrimoxazole reduces systemic inflammation in HIV infection by altering the gut microbiome and immune activation.

Long-term cotrimoxazole prophylaxis reduces mortality and morbidity in HIV infection, but the mechanisms underlying these clinical benefits are unclear. Here, we investigate the impact of cotrimoxazole on systemic inflammation, an independent driver of HIV mortality. In HIV-positive Ugandan and Zimbabwean children receiving antiretroviral therapy, we show that plasma inflammatory markers were lower after randomization to continue (n = 144) versus stop (n = 149) cotrimoxazole. This was not explained by clinical illness, HIV progression, or nutritional status. Because subclinical enteropathogen carriage and enteropathy can drive systemic inflammation, we explored cotrimoxazole effects on the gut microbiome and intestinal inflammatory biomarkers. Although global microbiome composition was unchanged, viridans group Streptococci and streptococcal mevalonate pathway enzymes were lower among children continuing (n = 36) versus stopping (n = 36) cotrimoxazole. These changes were associated with lower fecal myeloperoxidase. To isolate direct effects of cotrimoxazole on immune activation from antibiotic effects, we established in vitro models of systemic and intestinal inflammation. In vitro cotrimoxazole had modest but consistent inhibitory effects on proinflammatory cytokine production by blood leukocytes from HIV-positive (n = 16) and HIV-negative (n = 8) UK adults and reduced IL-8 production by gut epithelial cell lines. Collectively we demonstrate that cotrimoxazole reduces systemic and intestinal inflammation both indirectly via antibiotic effects on the microbiome and directly by blunting immune and epithelial cell activation. Synergy between these pathways may explain the clinical benefits of cotrimoxazole despite high antimicrobial resistance, providing further rationale for extending coverage among people living with HIV in sub-Saharan Africa.

Children With Noncritical Infections Have Increased Intestinal Permeability, Endotoxemia and Altered Innate Immune Responses.

BACKGROUND: Children with critical illness have increased intestinal permeability and a period of immunoparalysis, mediated by elevated circulating endotoxin. Whether children with less severe infections have similar changes is uncertain. METHODS: We conducted a proof-of-concept pilot study, enrolling children 6-59 months of age hospitalized for noncritical infections (cases, n = 11) and noninfected controls (n = 19). Intestinal permeability was measured by lactulose-mannitol recovery. Plasma endotoxin, blood monocyte and neutrophil immunophenotypes and cytokine elaboration following 24-hour whole-blood culture with antigens targeting distinct innate pathogen recognition receptor signaling pathways were evaluated. RESULTS: Cases had higher intestinal permeability and plasma endotoxin levels than controls. Among cases versus controls, fewer monocytes expressed human leukocyte antigen DR isotype (HLA-DR) (87.1% vs. 96.4%, P = 0.001), and more expressed CD64 (99.6% vs. 97.6%, P = 0.041). Following zymosan stimulation of whole blood, cases versus controls produced less interleukin 1 beta (IL-1ß) (median 1101 vs. 2604 pg/mL, P = 0.048) and tumor necrosis factor alpha (TNF-α) (2342 vs. 5130 pg/mL, P = 0.031). Children with higher (≥0.1 endotoxin unit (EU)/mL) versus lower (<0.1 EU/mL) circulating endotoxin had fewer monocytes expressing CD86 (69.8% vs. 92.4%, P = 0.003) and less expression of CD64 following 24-hour zymosan stimulation (median fluorescence intensity (MFI) 1514 vs. 2196, P = 0.022). CONCLUSIONS: Children hospitalized with noncritical infections had increased intestinal permeability, endotoxemia and altered monocyte phenotype and function. Collectively, these changes are typical of immunoparalysis seen in children with critical illness and may increase the risk of subsequent infections.

Health Outcomes, Pathogenesis and Epidemiology of Severe Acute Malnutrition (HOPE-SAM): rationale and methods of a longitudinal observational study.

INTRODUCTION: Mortality among children hospitalised for complicated severe acute malnutrition (SAM) remains high despite the implementation of WHO guidelines, particularly in settings of high HIV prevalence. Children continue to be at high risk of morbidity, mortality and relapse after discharge from hospital although long-term outcomes are not well documented. Better understanding the pathogenesis of SAM and the factors associated with poor outcomes may inform new therapeutic interventions. METHODS AND ANALYSIS: The Health Outcomes, Pathogenesis and Epidemiology of Severe Acute Malnutrition (HOPE-SAM) study is a longitudinal observational cohort that aims to evaluate the short-term and long-term clinical outcomes of HIV-positive and HIV-negative children with complicated SAM, and to identify the risk factors at admission and discharge from hospital that independently predict poor outcomes. Children aged 0-59 months hospitalised for SAM are being enrolled at three tertiary hospitals in Harare, Zimbabwe and Lusaka, Zambia. Longitudinal mortality, morbidity and nutritional data are being collected at admission, discharge and for 48 weeks post discharge. Nested laboratory substudies are exploring the role of enteropathy, gut microbiota, metabolomics and cellular immune function in the pathogenesis of SAM using stool, urine and blood collected from participants and from well-nourished controls. ETHICS AND DISSEMINATION: The study is approved by the local and international institutional review boards in the participating countries (the Joint Research Ethics Committee of the University of Zimbabwe, Medical Research Council of Zimbabwe and University of Zambia Biomedical Research Ethics Committee) and the study sponsor (Queen Mary University of London). Caregivers provide written informed consent for each participant. Findings will be disseminated through peer-reviewed journals, conference presentations and to caregivers at face-to-face meetings.

Schistosomiasis in the first 1000 days.

Infections during the first 1000 days-the period from conception to a child's second birthday-can have lifelong effects on health, because this is a crucial phase of growth and development. There is increasing recognition of the burden and potential effects of schistosomiasis in women of reproductive age and young children. Exposure to schistosomes during pregnancy can modulate infant immune development and schistosomiasis can occur from early infancy, such that the high disease burden found in adolescents is often due to accumulation of infections with long-lived schistosomes from early life. Women of reproductive age and young children are largely neglected in mass drug administration programmes, but early treatment could avert subsequent disease. We evaluate the evidence that early schistosomiasis has adverse effects on birth, growth, and development. We also discuss the case for expanding public health interventions for schistosomiasis in women of reproductive age and preschool-age children, and the need for further research to evaluate the potential of treating women pre-conception to maximise health across the life course.