Abstract Background Infants born HIV-exposed yet remain uninfected (HEU) are at increased risk of poorer growth and health compared to infants born HIV-unexposed (HU). Whether maternal antiretroviral treatment (ART) in pregnancy ameliorates this risk of poorer growth is not well understood. Furthermore, whether risks are similar across high burden HIV settings has not been extensively explored. Methods We harmonized data from two prospective observational studies conducted in Cape Town, South Africa, and Lusaka, Zambia, to compare weight-for-age (WAZ), length-for-age (LAZ) and weight-for-length (WLZ) Z-scores between infants who were HEU and HU, converting infant anthropometric measures using World Health Organisation Growth Standards adjusted for age and sex. Linear mixed effects models were fit to identify risk factors for differences in anthropometrics at 6–10 weeks and 6 months by infant HIV exposures status and by timing of exposure to maternal ART, either from conception or later in gestation. Results Overall 773 mother-infant pairs were included across two countries: women living with HIV (WLHIV), 51% ( n = 395) with 65% on ART at conception and 35% initiating treatment in pregnancy. In linear mixed effects models, WAZ and WLZ at 6–10 weeks were lower among infants who were HEU vs HU [β = − 0.29 (95% CI: − 0.46, − 0.12) and [β = − 0.42 (95% CI: − 0.68, − 0.16)] respectively after adjusting for maternal characteristics and infant feeding with a random intercept for country. At 6 months, LAZ was lower [β = − 0.28 CI: − 0.50, − 0.06)] among infants who were HEU, adjusting for the same variables, with no differences in WAZ and WLZ. Within cohort evaluations identified different results with higher LAZ among infants who were HEU from Zambia at 6–10 weeks, [β = + 0.34 CI: + 0.01, + 0.68)] and lower LAZ among infants who were HEU from South Africa [β = − 0.30 CI: − 0.59, − 0.01)] at 6 months, without other anthropometric differences at either site. Conclusion Infant growth trajectories differed by country, highlighting the importance of studying contextual influences on outcomes of infants who were HEU.
Successful vertical HIV transmission prevention programmes (VTP) have resulted in an expanding population of HIV-exposed uninfected (HEU) infants whose growth, health and neurodevelopmental outcomes could have consequences for future resource allocation. We compared neurodevelopmental and behavioural outcomes in a prospective cohort of 2–3 year old HEU and HIV-unexposed uninfected (HU) children.Women living with and without HIV and their infants were enrolled within three days of birth from a low-risk midwife obstetric unit in Cape Town, South Africa during 2012 and 2013, under WHO Option A VTP guidelines. HIV-uninfected children aged 30–42 months were assessed using the Bayley scales of Infant Development-Third edition (BSID) and Strengths and Difficulties questionnaire (SDQ).Thirty-two HEU and 27 HU children (mean birth weight 3048g vs 3096g) were assessed. HEU children performed as well as HU children on BSID cognitive, language and motor domains. Mean scores fell within the low average range. Mothers of HEU children reported fewer conduct problems but stunting was associated with increased total difficulties on the SDQ.HEU and HU children's performance on the BSID was similar. In this low-risk cohort, HIV exposure did not confer additional risk. Stunting was associated with increased behavioural problems irrespective of HIV exposure.
After witnessing an episode of poor injection safety in large numbers of children in a rural under-resourced hospital in Uganda, we briefly review our own experience and that of others in investigating HIV infection in children considered unlikely to be through commonly identified routes such as vertical transmission, sexual abuse or blood transfusion. In the majority of cases, parents are HIV uninfected. The cumulative experience suggests that the problem is real, but with relatively low frequency. Vertical transmission is the major route for HIV to children. However, factors such as poor injection safety, undocumented surrogate breast feeding, an HIV-infected adult feeding premasticated food to a weaning toddler, poor hygienic practice in the home and using unsterilised equipment for minor surgical or traditional procedures are of cumulative concern.
In 2012, of 1.5 million infants born to HIV-infected mothers globally, 250,000 acquired HIV, allowing estimation of the HIV-exposed uninfected (HEU) population.1 Many studies show higher rates of mortality and morbidity in HEU than HIV-unexposed (HU) children. For example, in the large Zimbabwe Vitamin A for Mothers and Babies Project (ZVITAMBO) conducted between 1997 and 2001, before combination antiretroviral therapy (cART) and trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis were available, mortality in HEU (8.1%) was almost 4-fold higher that in HU infants (2.2%).2 Increased incidence of lower respiratory tract infections and mucocutaneous candidiasis in HEU infants were observed.3 RISK FACTORS HIV in Pregnancy Maternal well-being influences infant health. Prematurity, low birth weight and small for gestation, all risk factors for infant mortality, are associated with maternal HIV infection. In a large retrospective study from Botswana, maternal HIV infection was associated with small for gestational age (odds ratio, 1.8: 1.7–1.9) and preterm delivery (odds ratio, 1.3: 1.3–1.4), after adjusting for maternal age, nulliparity, hypertension in pregnancy and anemia.4 In Zambia, Kuhn et al. showed that infants of mothers with CD4+ T cell counts <350 cells/mL were more likely to die (hazard ratio, 2.87; 95% confidence interval [CI], 1.03–8.03) or be hospitalized (hazard ratio, 2.28; 95% CI, 1.17–4.45) after adjusting for maternal death and low birth weight. In the ZVITAMBO study, a maternal CD4+ T cell count >800 cells/mm3 was found to be protective against infectious diseases morbidity.3 Maternal immunosuppression predisposes to congenital and perinatally acquired infections, which includes Mycobacterium tuberculosis, cytomegalovirus (CMV), syphilis, hepatitis B virus (HBV) and hepatitis C virus (HCV). Infant Feeding Breast-feeding is protective throughout the first 2 years of life, and especially in early infancy. As breast-feeding contributes to vertical transmission of HIV, replacement feeding using infant formula milks is recommended when accessible, feasible, affordable, sustainable and safe.5 However, in the areas where most HEU infants live, formula feeding is not a safe option. In a dramatic example highlighting the disadvantages of formula use in this setting, in a single hospital in Botswana during a diarrhea outbreak, 69 of 141 children requiring hospitalization for severe diarrhea were formula-fed HEU infants.6 Lack of Vaccine-induced Antibodies in the First Few Months of Life At birth and until the first immunizations are given, HEU infants were shown to have very low levels of antibodies (ie, below the threshold for protection) to pertussis, tetanus, pneumococcus and Haemophilus influenzae type B, partly explaining increased vulnerability to infectious diseases.7 In a second study from the same area (Cape Town), HEU infants also had low antibody levels to measles and HBV. However, HEU infants responded well to vaccines and for pertussis, responded better than HU infants.8 SPECIFIC DISEASES Tuberculosis Maternal tuberculosis can have grave consequences for infants. Pillay et al. described vertical M. tuberculosis transmission in 11 (14%) of 82 mothers coinfected with HIV and TB. Prematurity and intrauterine growth retardation occurred commonly.9 In a report from Cape Town, 27 of 41 infants whose mothers had TB and 6 of 8 infants with congenital TB were HEU. Median gestational age of TB-exposed infants was 36 (interquartile range, 33–38) weeks, and birth weight was 1.950 kg (interquartile range, 1.537–2.283 kg). The majority of mothers were only investigated once TB was clinically suspected.10 In a double-blinded randomized trial comparing preexposure isoniazid versus placebo in HIV-infected and HEU infants in Southern Africa between 2004 and 2008, isoniazid had no effect on TB incidence. Infants were enrolled between 3 and 4 months of age. In HEU children, the incidence of pulmonary TB was 4100 per 100,000 child years, a third of that in HIV-infected children.11 Comparing TB incidence in HEU infants with that from a Bacille Calmette-Guérin trial in South Africa between 2001 and 2004 where the rate in children below 2 years of age was 866 per 100,0000 child years,12 HEU infants appear to have a 4-fold higher risk of TB disease. Pneumocystis jirovecii Pneumonia Pneumocystis jirovecii, a well-recognized cause of severe pneumonia in HIV-infected infants, peaks between 3 and 6 months of age if no intervention occurs. P. jirovecii pneumonia (PCP) was recognized in HEU infants in 1997, when a report described 2 infants in Houston, TX, presenting with PCP at around 50 days of age.13 Since then PCP has been identified in small numbers of HEU infants in South Africa.14 Cytomegalovirus Congenital CMV is a leading cause of hearing loss in children. In a recent study from Cape Town, 22 (2.9%) of 748 HEU infants had congenital CMV infection. Maternal CD4 count <200 cells/mm3 was the major risk factor for congenital CMV infection in multivariate analysis. Antenatal cART, present in 50% of the cohort, was found not to be protective.15 CMV colitis, necessitating bowel resection, has been described in an HEU infant aged 7 months with chronic diarrhea. Malnutrition may have contributed to severe CMV infection.14 Syphilis, Herpes Simplex-2 Virus, HBV and HBC These infections can be sexually transmitted. Unsuspected syphilis and herpes simplex-2 virus (HSV-2) infection either at labor or in the postpartum period was demonstrated in stored specimens from mothers in the ZVITAMBO study.16 Using a similar approach in Malawi, 119 (5.9%) of 2048 mothers of HEU infants had active HBV infection with 5 infants acquiring HBV by week 48.17 In New York City, 6 (12.8%) of 47 HEU infants whose mothers had HCV acquired HCV vertically in a retrospective study.18 CHANGING CIRCUMSTANCES—INCREASED USE OF CART FOR PREVENTION OF MOTHER TO CHILD TRANSMISSION IN AFRICA With more pregnant women accessing cART earlier and with higher CD4 counts and also integration of TB and HIV services, maternal health in HIV-infected women should continue to improve, likely with secondary benefits for HEU infants. However, increased exposure to antiretrovirals may have risks. For example, in Botswana, compared with zidovudine alone, nevirapine-based cART resulted in higher odds for preterm delivery (adjusted odds ratio, 1.4; 95% CI, 1.2–1.8) and small for gestational age (adjusted odds ratio, 1.5; 95% CI, 1.2–1.9).4 APPROACH HEU children require regular follow-up. The following should be addressed: For infant feeding, replacement feeding should be assessed according to accessible, feasible, affordable, sustainable and safe criteria. In most high HIV prevalence settings, exclusive breast-feeding for 6 months followed by gradual weaning, with protection through antiretrovirals, is essential. Maternal screening should take place for syphilis, HSV-2, HBV and HCV. Regional prevalence should guide decisions for HBV and HCV testing. Congenital CMV infection, with its risk for sensorineural hearing loss, requires screening in the first 3 weeks of life. PCP occasionally occurs in young HEU infants. Current World Health Organization guidelines recommend discontinuing TMP-SMX prophylaxis after exclusion of HIV infection in non–breast-feeding infants. Where formula feeding is the norm, TMP-SMX should continue until the HIV polymerase chain reaction test at 4 months of age is negative. In high HIV prevalence settings, prophylaxis should continue until the infant is fully weaned and HIV infection is excluded. TMP-SMX should continue to be given to HEU infants in malaria endemic areas.19 Currently, data from a randomized trial in rural Uganda show moderate efficacy until 2 years of age.20 In areas with high TB prevalence, mothers should be actively screened for TB, and if found to have active TB, their infants should be investigated. In the absence of disease in the infant, postexposure prophylaxis according to country guidelines is appropriate. Lastly, HEU infants and children remain at risk for acquiring HIV. Breast-feeding, particularly if the mother is nonadherent regarding either her own cART or giving the infant prophylactic nevirapine, is a risk. Also, premastication of food by a HIV-infected carer for a weaning infant has been implicated in HIV transmission and should be avoided, when feeding HEU infants.21 AREAS FOR RESEARCH Many aspects require more data. The potential impact of sexually transmitted infections such as HSV-2, syphilis, HBV and HCV on HEU infants requires further exploration. TB in high prevalence settings is still under-appreciated. The role of TMP-SMX in preventing PCP and malaria and its optimal duration in HEU infants require further investigation, as does potential poorer outcomes in pregnancy linked to cART. Duration of response to immunization requires longer-term follow-up. Lastly, biological mechanisms resulting in increased vulnerability of HEU infants to infection require further exploration.
To the Editors: In the January 2019 issue of this journal, Dadabhai et al1 presented an analysis of birth outcomes, including preterm birth (PTB), low birth weight, and small for gestational age (SGA) among infants born to women living with HIV (WLHIV) on antiretroviral therapy (ART) compared with women without HIV, enrolled in the Pregnancy Outcomes and Infant Survival in the Era of Universal HAART in Africa (POISE) study. This comparison is crucial to understand whether the previously observed disparity in birth outcomes between women with and without HIV is being narrowed by maternal ART.2 In POISE, WLHIV were included if they were on ART for at least 1 week before delivery and had a delivery CD4 count ≥350 cells/mm3. Women were enrolled in the maternity ward either just before or after delivery, at one teaching hospital and 4 major health centers in Blantyre, Malawi, during 2016 and 2017. Of 5423 women approached, 614 WLHIV and 685 women without HIV were ultimately enrolled. Within the cohort of infants born to enrolled women, there was no difference in PTB, low birth weight, or SGA by maternal HIV status, and the paper concludes that “ART use has reduced the high rates of adverse pregnancy outcomes among HIV-infected women.”1 The authors considered the possibility of selection bias and thought it unlikely to be present or at least not to be differential between women with and without HIV. However, the methodology used for participant selection is likely to preferentially exclude women with adverse birth outcomes, particularly severe outcomes. Women approached in the postpartum period whose newborns were acutely ill or who died shortly after birth (often due to severe prematurity) may have been less likely to enroll in a 1-year prospective study of infant survival and may also not have been readily accessible for recruitment. For the same reasons, women approached before delivery in preterm labor, or with serious pregnancy complications, may have been less inclined to enroll and less accessible. Evidence for this type of selection bias is observed in the POISE study population, as the lowest birth weight of enrolled infants was 1.9 kg and the minimum gestational age was 34 weeks, highlighting the fact that no infant with very low birth weight (<1.5 kg) or born very preterm was included. Although lower enrollment with severe outcomes may have occurred regardless of maternal HIV-infection status, the included study population is no longer representative of the entire population. If PTB and lower birth weights occur more frequently in the newborns of WLHIV, then selection bias in the POISE study sample would lead to a bias toward the null in the comparison of PTB and low birth weight between WLHIV and women without HIV. Interestingly, the POISE study did find differences in some of the SGA outcomes by HIV status. SGA, which is associated with less immediate morbidity than very PTB or very low birth weight among neonates, may therefore be less susceptible to selection bias. Recent studies from Botswana and South Africa have indeed shown that compared with women without HIV, WLHIV and on ART have an increased risk of adverse birth outcomes, particularly PTB.3,4 There are important methodological differences between these studies and POISE. The Tsepamo study in Botswana reported increased risk of PTB [adjusted risk ratio 1.18; 95% confidence interval (CI): 1.12 to 1.25] and SGA (adjusted risk ratio 1.30; 95% CI: 1.23 to 1.38) among women on efavirenz-based ART compared with women without HIV.3 Like POISE, Tsepamo collected maternal pregnancy and birth outcome data shortly after delivery, but in Botswana, the data were abstracted on all consecutive deliveries at 8 government hospitals.3 By including all deliveries at the study facilities and not a selected sample as in POISE, the risk of selection bias was minimized. The South African study, which enrolled pregnant women at their first antenatal care visit, observed double the odds of PTB in WLHIV initiating ART during pregnancy compared with women without HIV (adjusted odds ratio 2.03; 95% CI: 1.33 to 3.10).4 Antenatal enrollment well before the end of pregnancy with prospective follow-up for complete outcome ascertainment guards against noninclusion of women with worse birth outcomes. The likely selection bias introduced by the design of the POISE study and conducted in a single African country should not provide stakeholders with definitive reassurance or causal evidence that maternal ART has mitigated adverse pregnancy outcomes among WLHIV in sub-Saharan Africa.
We aimed to quantify the contribution of excess mortality in HIV-exposed uninfected (HEU) infants to total mortality in HIV-uninfected infants in Botswana and South Africa in 2013. Population attributable fractions (PAFs) and excess infant deaths associated with HIV exposure in HIV-uninfected infants were estimated. Additionally, the Thembisa South African demographic model estimated the proportion of all infant mortality associated with excess mortality in HEU infants from 1990 to 2013. The PAF (lower bound; upper bound) of mortality associated with HIV exposure in HIV-uninfected infants was 16.8% (2.5; 31.2) in Botswana and 15.1% (2.2; 28.2) in South Africa. Excess infant deaths (lower bound; upper bound) associated with HIV exposure in 2013 were estimated to be 5.6 (0.5; 16.6)/1000 and 4.9 (0.6; 11.2)/1000 HIV-uninfected infants in Botswana and South Africa, respectively. In South Africa, the proportion of all infant (HIV-infected and HIV-uninfected) mortality associated with excess HEU infant mortality increased from 0.4% in 1990 to 13.8% in 2013.
Abstract Introduction Co‐trimoxazole prophylaxis is recommended for children born to women with HIV to protect those who acquire HIV from opportunistic infections, severe bacterial infections and malaria. With scale‐up of maternal antiretroviral therapy, most children remain HIV‐exposed uninfected (HEU) and the benefits of universal co‐trimoxazole are uncertain. We assessed the effect of co‐trimoxazole on mortality and morbidity of children who are HEU. Methods We performed a systematic review (PROSPERO number: CRD42021215059). We systematically searched MEDLINE, Embase, Cochrane CENTRAL, Global Health, CINAHL Plus, Africa‐Wide Information, SciELO and WHO Global Index Medicus for peer‐reviewed articles from inception to 4th January 2022 without limits. Ongoing randomized controlled trials (RCTs) were identified through registries. We included RCTs reporting mortality or morbidity in children who are HEU receiving co‐trimoxazole versus no prophylaxis/placebo. The risk of bias was assessed using the Cochrane 2.0 tool. Data were summarized using narrative synthesis and findings were stratified by malaria endemicity. Results We screened 1257 records and included seven reports from four RCTs. Two trials from Botswana and South Africa of 4067 children who are HEU found no difference in mortality or infectious morbidity in children randomized to co‐trimoxazole prophylaxis started at 2–6 weeks of age compared to those randomized to placebo or no treatment, although event rates were low. Sub‐studies found that antimicrobial resistance was higher in infants receiving co‐trimoxazole. Two trials in Uganda investigating prolonged co‐trimoxazole after breastfeeding cessation showed protection against malaria but no other morbidity or mortality differences. All trials had some concerns or a high risk of bias, which limited the certainty of evidence. Discussion Studies show no clinical benefit of co‐trimoxazole prophylaxis in children who are HEU, except to prevent malaria. Potential harms were identified for co‐trimoxazole prophylaxis leading to antimicrobial resistance. The trials in non‐malarial regions were conducted in populations with low mortality potentially reducing generalizability to other settings. Conclusions In low‐mortality settings with few HIV transmissions and well‐performing early infant diagnosis and treatment programmes, universal co‐trimoxazole may not be required.
COVID-19 in pregnancy inSouth Africa: Tracking the epidemic and defining the natural history Proposed sentinel site surveillance of COVID-19 in pregnant women.The figure represents diverse environments including high-rise buildings, informal settlements, RDP (government subsidy) housing and the potential for pregnant women to represent COVID-19 infection within the broader population.(Red dots = COVID-19 infection; green dots = COVID-19-uninfected; ANC clinic = antenatal clinic.)
Objectives: Infants who are HIV exposed but uninfected (HEU) compared with HIV unexposed uninfected (HUU) have an increased risk of adverse birth outcomes, morbidity and hospitalization. In the era of universal maternal antiretroviral treatment, there are few insights into patterns of neonatal morbidity specifically. Design: A prospective cohort study. Methods: We compared neonatal hospitalizations among infants who were HEU ( n = 463) vs. HUU ( n = 466) born between 2017 and 2019 to a cohort of pregnant women from a large antenatal clinic in South Africa. We examined maternal and infant factors associated with hospitalization using logistic regression. Results: Hospitalization rates were similar between neonates who were HEU and HUU (13 vs. 16%; P = 0.25). Overall, most hospitalizations occurred directly after birth (87%); infection-related causes were identified in 34%. The most common reason for hospitalization unrelated to infection was respiratory distress (25%). Very preterm birth (<32 weeks) (29 vs. 11%; P = 0.01) as well as very low birthweight (<1500 g) (34 vs. 16%; P = 0.02) occurred more frequently among hospitalized neonates who were HEU. Of those hospitalized, risk of intensive care unit (ICU) admission was higher in neonates who were HEU (53%) than HUU (27%) [risk ratio = 2.1; 95% confidence interval (95% CI) 1.3–3.3]. Adjusted for very preterm birth, the risk of ICU admission remained higher among neonates who were HEU (aRR = 1.8; 95% CI 1.1–2.9). Conclusion: Neonates who were HEU (vs. HUU) did not have increased all-cause or infection-related hospitalization. However, very preterm birth, very low birthweight and ICU admission were more likely in hospitalized neonates who were HEU, indicating increased severity of neonatal morbidity.
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