Abstract
Objectives:
We described and compared infectious-cause hospitalisation outcomes among children born without HIV in the Western Cape (WC), South Africa, during the WHO Option B+ (2013–2015) and universal ART (2016–2018) eras by exposure to maternal HIV and ART.
Design:
Retrospective cohort.
Methods:
Using data from the WC Provincial Health Data Centre, we described rates, causes and risk factors of infectious-cause hospitalisations, up to age 3 years, among children born at a public WC health facility. We compared rates of and risk factors for admission, in children exposed to maternal HIV and uninfected (HEU) and children HIV unexposed and uninfected (HUU), in the neonatal, post-neonatal (age >28 days to ≤12 months), and age >12–36 month periods using mixed-effects Poisson regression. Regression models were adjusted for maternal age and suburb of residence.
Results:
We included 398,334 mother-child pairs, 17.2% children HEU and 82.8% HUU. Infectious-cause hospitalisation, between birth and age 3 years, occurred in 11.5% vs. 10.9% of children HEU and HUU respectively. Children HEU experienced higher rates of hospitalisation than children HUU, irrespective of maternal ART history, during the neonatal period (adjusted incidence rate ratios, aIRRs: 1.34–1.66) and post-neonatal period (aIRRs: 1.13–1.42), but not during the >12–36 month period. Among children HEU, maternal VL ≥1000/mL vs. <1000/mL during pregnancy was associated with higher admission rates during the post-neonatal period (aIRR=1.15; 95% CI:1.06–1.25).
Conclusions:
Irrespective of timing of maternal ART start, children HEU vs. HUU had higher rates of infectious-cause hospitalisation during the first year of life, but not thereafter.
Keywords: HIV exposure, infectious-cause, hospitalisation, children HEU, South Africa
Introduction
In South Africa, due to high maternal HIV prevalence and a very successful prevention of vertical HIV transmission programme, 1 in 5 children is exposed to maternal HIV but uninfected (HEU)[1]. Studies suggest that children HEU have higher risk of infectious morbidity than children HIV unexposed and uninfected (HUU)[2–8]. The relative risk of hospital admission appears greatest from one to 12 months of age, possibly due to more severe infections in children HEU, while neonatal admission rates are similar between groups[3,8–10].
Admissions of greater severity increases the burden on hospitals and intensive care units (ICU), affecting care for all children[11,12]. Understanding health disparities in children HEU is a priority for HIV high-prevalence settings, not only to reduce the burden on healthcare services, but to ensure they survive and thrive in adolescence and adulthood[13].
Many studies comparing infectious-cause outcomes in children HEU vs. HUU predate the WHO “Option B+” (immediate antiretroviral therapy (ART) for all pregnant women living with HIV) and universal ART access (ART for all people living with HIV regardless of clinical or immunological stage) eras. Furthermore, study sample sizes have been small and often restricted to single healthcare facilities, limiting the statistical power to observe true differences between groups.
Using province-wide electronic healthcare data we described characteristics, causes, rates of, and factors associated with infectious-cause hospital admissions in children ≤3 years old born without HIV in the Western Cape (WC), South Africa (SA) and compared rates of hospitalisation by exposure to maternal HIV and ART.
Methods:
Study design and data source
This retrospective, population-based, cohort study used routine electronic maternal and child healthcare data from the Western Cape Provincial Health Data Centre (WCPHDC), a digital health information exchange that consolidates multiple sources of individual-level data from provincial public-sector health service systems in the WC using unique patient health identifiers[14].
Study setting
The WC, one of SA’s nine provinces, has an estimated population size of 7.4 million approximately three quarters of which utilise public-sector health services, including most people with HIV [15].
Antenatal HIV prevalence in the WC was estimated to be 18% in 2019[16].
Study participants
We included all children with a recorded live birth in the WCPHDC between January 2013 and December 2018 (Figure, Supplemental Digital Content 1). Children were excluded if they were known to have HIV by age 10 weeks, or if HIV was first recorded after 10 weeks with no prior negative test record. We additionally excluded children if: maternal HIV was first recorded >10 weeks and <3 years post-delivery (uncertain child exposure); they were not electronically linked to their mothers; or if diagnostic data were inconsistent (e.g. HIV-PCR negative after first HIV evidence date).
Procedures and measurements
We used mother-child WCPHDC data on maternal suburb of residence, maternal age, parity, birth and death dates, child sex, birthweight, multiple pregnancies (twins/triplets), and laboratory HIV test results (HIV-PCR and HIV-antigen/antibody/Rapid tests). For children HEU, we included maternal data on first HIV evidence date, ART start and dispensing dates, CD4 cell count and HIV viral load (VL) measurements/results. For infectious-cause admissions, we extracted admission and discharge dates, causes of admission, and ICU stays.
Follow-up:
Children were followed up from date of birth until the earliest date of: last negative HIV test result if subsequently diagnosed with HIV, death, or age three years. Time spent in hospital following an infectious-cause admission was excluded from follow-up time.
Exposure:
Children were classified as in utero HUU if their mothers had no evidence of HIV or first evidence of was after the child’s third birthday, and as HEU if maternal HIV first evidence was ≤10 weeks after birth. We used simplified DECIPHER (Data Evaluation and Collaborative Initiation for Paediatric HIV Education and Research) Project definitions (Table, Supplemental Digital Content 2) to determine the certainty (high, moderate, low, no certainty) of in utero HIV exposure and infection status at the end of follow-up. The applicability of these simplified DECIPHER definitions to this routine healthcare dataset has been described previously[17,18].
For regression models, we stratified children HEU by timing of maternal ART start and dispensing relative to pregnancy start (approximated as 42 weeks before child date of birth) and, for mothers who started ART before pregnancy, whether they started ART before or after universal ART availability from 2016 onwards (Table, Supplemental Digital Content 2).
Outcomes:
The primary outcome was the number of child infectious-cause hospital admissions during follow-up. Infectious causes included lower respiratory tract infections (LRTI), diarrhoea, meningitis, and tuberculous meningitis (TBM), classified within the WCPHDC using ICD-10 codes[19]. Other infectious-causes were not included as the algorithms to classify them within the WCPHDC were less robust. For children with multiple infectious diagnoses at a single admission, the primary cause was assigned in the order of TBM, meningitis, LRTI, diarrhoea prioritising the condition with most severe long-term consequences. Admissions within 21 days of discharge were considered part of the same hospitalisation episode.
Confounders:
We considered maternal age at delivery and socioeconomic status as potential confounders a priori using a directed acyclic graph (Figure, Supplemental Digital Content 3). Mother’s suburb of residence at time of data extraction (2022) was used as a proxy for socioeconomic status and was grouped into Cape Town District versus other districts (Cape Winelands, Central Karoo, Garden Route, Overberg and West Coast district) to describe area of residence.
Factors associated with infectious-cause hospital admissions:
Other potentially associated factors included were maternal age, child sex, birthweight (coded as: macrosomia (≥4000g); normal (2500 - <4000g); low (1500 - <2500g); very low (1500 - <2500g)), multiple pregnancy status, parity and season of birth (Figure, Supplemental Digital Content 3).
Among children HEU, we additionally considered maternal VL (coded as <1000 copies/mL, ≥1000 copies/mL) and CD4 cell count (<350 cells/μL, ≥350 cells/μL) nearest to pregnancy start, within 42 weeks pre-delivery and 90 days post-delivery, as individual factors potentially associated with admissions.
Statistical analyses
We described key maternal, child and hospitalisation characteristics, by exposure to maternal HIV, using proportions for categorical variables and means with standard deviations or medians with first and third quartiles for non-skewed and skewed continuous variables respectively. We compared maternal and child characteristics by HIV exposure status using Chi-squared tests for categorical variables and two-sample t-tests for non-skewed continuous variables.
Infectious-cause hospitalisation incidence rates (per 100 child-years) among children HEU and HUU, regardless of timing of maternal ART start, were compared using crude incidence rate ratios (IRRs) both overall and stratified by child age: early neonatal (age 0 – 6 days), late neonatal (age 7 – 27 days); post-neonatal (age 28 days – 12 months), age >12 – 24 months, age >24 – 36 months.
We fitted two sets of mixed effect Poisson regression models, each stratified by age period (neonatal (≤28 days), post-neonatal (>28 days – 12 months, and >12 – 36-months). The first set explores the association between HIV/ART exposure group and infectious disease hospital admissions. Here we present unadjusted incidence rate ratios (uIRRs) and incidence rate ratios adjusted (aIRRs) for the two confounders. For this set of models, we performed sensitivity analyses to assess a) adjusted associations between HIV/ART exposure and admission count when including only children classified HEU or HUU with high-moderate certainty, and b) the potential mediating effect of birthweight on admissions. The second set of regression models explores factors potentially associated with infection-related admissions (apart from HIV/ART exposure) in children HEU and HUU separately. Here we present uIRRs and aIRRs for each of the factors. All models included child-level (i.e. child identifier) random effects. Multivariable models containing suburb of residence also included it as a random effect.
We described frequencies and proportions of missing data. For variables maternal ART start, VL, and CD4 cell count, we included a “no evidence” (missing) category for analyses. For other variables, we used complete case analysis. Analyses were done using Stata 17.0[20].
Ethics
The University of Cape Town Human Research Ethics Committee approved this study (REF 101/2021) of de-identified routinely collected data, including a waiver of informed consent.
Results
Child, mother and hospitalisation characteristics
407,342 live births were recorded in the WCPHDC between 2013 and 2018, of which 398,334 (97.8%) children were included for analyses (Figure, Supplemental Digital Content 1). Characteristics of children and mothers are shown in Table 1 and Table 2. At the start of follow-up, 17.2% and 82.8% of children were classified as HEU and HUU respectively. Among children HEU, 1.0%, 68.8%, and 13.8% were classified with high, moderate, and low certainty of living without HIV at the end of follow-up, respectively (Table, Supplemental Digital Content 4). Among children HEU and HUU, 17.9% and 16.0% had low birthweights (<2500g) (Table 1). Amongst children HEU born <2016 and ≥2016, 34.7% and 54.1% of mothers started ART before pregnancy, respectively (Table 2). Among mothers with data available, 86.3% of mothers who were on ART at pregnancy start had VL <1000 copies/mL nearest to pregnancy start.
Table 1:
Characteristics of children (and their mothers), born in Western Cape from 2013 – 2018, by exposure to maternal HIV and child HIV diagnosis status at the start of follow up (N=398,334)
| Variable | Total N=398,334 (100.0%) | Children HEU N=68,455 (17.2%) | Children HUU N=329,879 (82.8%) | p-value |
|---|---|---|---|---|
| Child characteristics | ||||
| Sex: n (%) | 0.130 | |||
| Male | 201,533 (50.6) | 34,608 (50.6) | 166,925 (50.6) | |
| Missing | 784 (0.2) | 156 (0.2) | 628 (0.2) | |
| Birthweight (g): n (%) | <0.001 | |||
| Foetal macrosomia (≥4000g) | 16,545 (4.2) | 2,308 (3.4) | 14,237 (4.3) | |
| Normal (2500 – <4000) | 315,714 (79.3) | 53,714 (78.5) | 262,000 (79.4) | |
| Low (1500 – <2500) | 53,848 (13.5) | 10,047 (14.7) | 43,801 (13.3) | |
| Very Low (1500 – <2500g) | 7,347 (1.8) | 1,559 (2.3) | 5,788 (1.8) | |
| Extremely Low (<1000g) | 3,600 (0.9) | 621 (0.9) | 2,979 (0.9) | |
| Missing | 1,280 (0.3) | 206 (0.3) | 1,074 (0.3) | |
| Mean (SD) | 3,025 (635) | 2,983 (637) | 3,034 (633) | <0.001 |
| Multiple pregnancy: n (%) | <0.001 | |||
| Yes | 11,045 (2.8) | 2,474 (3.6) | 8,571 (2.6) | |
| Missing | 144 (0.04) | 36 (0.05) | 108 (0.03) | |
| Birth year: n (%) | <0.001 | |||
| 2013 & 2014 | 101,552 (25.5) | 15,479 (22.6) | 86,073 (26.1) | |
| 2015 & 2016 | 135,710 (34.1) | 23,141 (33.8) | 112,569 (34.1) | |
| 2017 & 2018 | 161,072 (40.4) | 29,835 (43.6) | 131,237 (39.8) | |
| Season of birth ‡ : n (%) | 0.174 | |||
| Summer | 97,698 (24.5) | 16,970 (24.8) | 80,728 (24.5) | |
| Autumn | 98,015 (24.6) | 16,698 (24.4) | 81,317 (24.7) | |
| Winter | 100,519 (25.2) | 17,170 (25.1) | 83,349 (25.3) | |
| Spring | 102,102 (25.6) | 17,617 (25.7) | 84,485 (25.6) | |
| Died before 3 years of age (all-cause): n (%) | 0.001 | |||
| Yes | 4,547 (1.1) | 866 (1.3) | 3,681 (1.1) | |
| Child exposure to maternal HIV and HIV diagnosis at the end of follow-up: n (%) | <0.001 | |||
| HEU | 67,978 (17.1) | 67,978 (99.3) | 0 (0.0) | |
| HUU | 329,820 (82.8) | 0 (0.0) | 329,820 (99.9) | |
| Children with HIV | 413 (0.1) | 372 (0.5) | 41 (0.01) | |
| Unknown¥ | 123 (0.03) | 105 (0.2) | 18 (0.01) | |
| Maternal non-HIV-related characteristics | ||||
| Age at delivery (years): n (%) | <0.001 | |||
| 15 – 19 | 48,000 (12.1) | 2,358 (3.4) | 45,642 (13.8) | |
| 20 – 39 | 337,437 (84.7) | 63,431 (92.7) | 274,006 (83.1) | |
| 40 – 50 | 11,516 (2.9) | 2,608 (3.8) | 8908 (2.7) | |
| Missing: n (%) | 1,381 (0.4) | 58 (0.1) | 1,323 (0.4) | |
| Mean (SD) | 27.4 (6.2) | 29.8 (5.7) | 26.9 (6.2) | <0.001 |
| Area of residence: n (%) | <0.001 | |||
| Cape Town District | 269,648 (67.7) | 51,238 (74.8) | 218,410 (66.2) | |
| Other districts | 122,489 (30.8) | 16,348 (24.9) | 106,141 (32.2) | |
| Missing | 6,197 (1.6) | 869 (1.3) | 5,328 (1.6) | |
| Parity † : n (%) | <0.001 | |||
| 0 | 247,008 (62.0) | 38,530 (56.3) | 208,478 (63.2) | |
| 1 | 106,047 (26.6) | 20,718 (30.3) | 85,329 (25.9) | |
| 2 | 33,792 (8.5) | 7,046 (10.3) | 26,746 (8.1) | |
| ≥3 | 11,426 (2.9) | 2,149 (3.1) | 9,277 (2.8) | |
| Missing: n (%) | 61 (0.02) | 12 (0.02) | 49 (0.01) | |
| Maternal death by child age 3 years: n (%) | ||||
| Yes | 1,207 (0.3) | 631 (0.9) | 576 (0.2) | <0.001 |
Unknown child exposure to maternal HIV and HIV diagnosis status at end of follow-up are children whose HIV first evidence date was after age 3 years, but for whom date of acquisition is unknown
Parity is recorded during current pregnancy and is based on digital evidence of prior pregnancies in the Western Cape only. True parity may therefore be underestimated
Season defined as: Summer (December – February); Autumn (March – May); Winter (June – August); Spring (September – November)[7].
Abbreviations – ART: antiretroviral therapy; g: grams, HEU: exposed to maternal HIV and uninfected; HUU: unexposed to maternal HIV and uninfected; SD: standard deviation
Table 2:
Maternal HIV-related characteristics among children HEU born in Western Cape from 2013 – 2018
| Variable | Children HEU N=68,455 |
|---|---|
| Year of maternal ART start: n (%) | |
| <2013 | 15,359 (22.4) |
| 2013 – 2015 | 30,162 (44.1) |
| ≥2016 | 20,272 (29.6) |
| No ART evidence ever | 2,662 (3.9) |
| Timing of first maternal ART evidence n (%) | |
| Among children born <2016 (N=26,574) | |
| Before pregnancy | 9,220 (34.7) |
| During pregnancy | 12,912 (48.6) |
| Delivery/Postpartum | 3,348 (12.6) |
| No ART evidence ever | 1,094 (4.1) |
| Among children born ≥2016 (N=41,881) | |
| Before pregnancy | 22,648 (54.1) |
| During pregnancy | 15,590 (37.2) |
| Delivery/Postpartum | 2,075 (5.0) |
| No ART evidence ever | 1,568 (3.7) |
| Maternal ART start and dispensing relative to pregnancy: n (%) | |
| ART before pregnancy and start before Universal ART (<2016) | 19,600 (28.6) |
| ART before pregnancy and start during Universal ART (≥2016) | 2,499 (3.7) |
| ART restart during pregnancy | 6,140 (9.0) |
| ART start during pregnancy | 27,581 (40.3) |
| No ART during pregnancy¥ | 6,339 (9.3) |
| Unknown ART† | 3,634 (5.3) |
| No ART evidence ever | 2,662 (3.9) |
| First maternal viral load during pregnancy <1000 copies/mL: n (%) | |
| Among all women with HIV‡ (N=56,744) | 46,796 (82.5) |
| Among women on ART before pregnancy‡ (N=21,943) | 19,673 (89.7) |
| Among women not on ART before pregnancyঠ(N=33,485) | 26,076 (77.9) |
| No evidence* | 11,711 (17.1) |
| First maternal CD4 cell count during pregnancy ≥350 copies/μL: n (%) | |
| Among all women with HIV‡ (N=53,584) | 32,951 (61.5) |
| Among women on ART before pregnancy‡ (N=16,007) | 11,829 (73.9) |
| Among women not on ART before pregnancyঠ(N=36,150) | 20,233 (55.6) |
| No evidence* | 14,871 (21.7) |
| Median (Q1, Q3) | 413 (274, 577) |
Maternal ART start date at delivery or postpartum
Maternal ART start before or during pregnancy, but no electronic evidence of ART dispensing during pregnancy
Percentages are calculated as a proportion of those with a viral load or CD4 cell count measurement
Includes women who interrupted ART before pregnancy start and excludes women with no evidence of ART start
Percentages are calculated as a proportion of all children HEU
Abbreviations – ART: antiretroviral therapy; HEU: exposed to maternal HIV and uninfected; Q: quartile
Among children HEU and HUU, 11.5% and 10.9% had ≥1 infectious-cause hospitalisation between birth and age 3 years, respectively (Table, Supplemental Digital Content 5). Of all admissions, 2.9% and 1.6% of children HEU and HUU respectively had ICU admissions.
Causes of hospitalisation
Supplemental Digital Content 5 shows the distribution of the primary infectious cause of admissions, by exposure to maternal HIV. For all admissions between birth and age 3 years, LRTI was the most common cause of admission (children HEU: 63.7%; children HUU: 68.9%), followed by diarrhoea (children HEU: 39.8%; children HUU: 31.8%).
Infectious-cause hospitalisation rates
Admission rates were highest during the early neonatal period vs. later periods and similar for both children HEU (14.6/100 child years) and HUU (13.3/100 child years) (Table 3). The crude relative rate of admissions for children HEU vs. HUU was highest during the late neonatal period (IRR=1.57; 95% CI: 1.42–1.74). After age 1 year, HEU children had lower admission rates than children HUU (12 – 24 months IRR=0.92; 95% CI: 0.88–0.96; 24 – 30 months IRR =0.73; 95% CI 0.68–0.80).
Table 3:
Infectious-cause hospitalisations comparing children HEU and children HUU – crude incidence rates and incidence rate ratios per age interval
| Age category | All children | Children HEU | Children HUU | Crude IRR (95% CI) |
|---|---|---|---|---|
| Overall | ||||
| Number of children at risk | 398,334 | 68,455 | 329,879 | – |
| Number of admissions | 55,309 | 9,795 | 45,514 | – |
| Person-time (years) | 1178,524 | 201,508 | 977,016 | – |
| Incidence per 100 child years | 4.69 | 4.86 | 4.66 | 1.04 (1.02 – 1.07) |
| 0 – 6 days | ||||
| Number of children at risk | 398,334 | 68,455 | 329,879 | – |
| Number of admissions | 1,024 | 191 | 833 | – |
| Person-time (years) | 7,590 | 1,305 | 6,285 | – |
| Incidence per 100 child years | 13.49 | 14.64 | 13.25 | 1.10 (0.94 – 1.29) |
| 7 – 27 days | ||||
| Number of children at risk | 395,236 | 67,922 | 327,314 | – |
| Number of admissions | 2,034 | 499 | 1,535 | – |
| Person-time (years) | 22,636 | 3,886 | 18,750 | – |
| Incidence per 100 child years | 8.99 | 12.84 | 8.19 | 1.57 (1.42 – 1.74) |
| 28 days – 12 months | ||||
| Number of children at risk | 395,170 | 67,901 | 327,269 | – |
| Number of admissions | 30,883 | 5,887 | 24,996 | – |
| Person-time (years) | 362,637 | 62,026 | 300,610 | – |
| Incidence per 100 child years | 8.52 | 9.49 | 8.03 | 1.14 (1.11 – 1.17) |
| >12 months – 24 months | ||||
| Number of children at risk | 393,731 | 67,315 | 326,416 | – |
| Number of admissions | 14,832 | 2,358 | 12,474 | – |
| Person-time (years) | 392,629 | 67,111 | 325,518 | – |
| Incidence per 100 child years | 3.78 | 3.51 | 3.82 | 0.92 (0.88 – 0.96) |
| >24 months – 36 months | ||||
| Number of children at risk | 393,476 | 67,244 | 326,232 | – |
| Number of admissions | 6536 | 860 | 5676 | – |
| Person-time (years) | 393,032 | 67,180 | 325,852 | – |
| Incidence per 100 child years | 1.66 | 1.28 | 1.74 | 0.73 (0.68 – 0.80) |
Abbreviations – HEU: exposed to maternal HIV and uninfected; HUU: unexposed to maternal HIV and uninfected; IRR: Incidence rate ratio
When stratifying children HEU by timing of maternal ART start, univariable analysis found that, during the neonatal period, the risk of infectious-cause hospitalisation was higher among children HEU compared to children HUU if their mothers a) started ART before pregnancy but prior to Universal ART (uIRR=1.38; 95% CI: 1.10–1.60), b) restarted ART during pregnancy (uIRR=1.50; 95% CI: 1.17–1.91), c) started ART during pregnancy (uIRR=1.41; 95% CI: 1.24–1.60), or d) were on no ART during pregnancy (uIRR=1.48; 95% CI: 1.16–1.89) (Table 4A). During the post-neonatal period, the increased risk of hospitalisation among children HEU relative to HUU persisted in the same maternal ART timing groups, although the magnitude of this increased risk among children whose mothers started ART during pregnancy was substantially smaller (uIRR=1.06; 95% CI: 1.01–1.11). Relative to children HUU, the highest IRRs across the neonatal and post-neonatal periods were observed in children HEU whose mothers restarted ART during pregnancy after an ART gap, or were not on ART during pregnancy. During the >12 – 36 months period, children HEU whose mothers started ART before or during pregnancy, or had no evidence of ART ever, had reduced rates of hospitalisation relative to children HUU.
Table 4:
Mixed effects Poisson regression models assessing the association between HIV/ART exposure and infectious-cause hospitalisation in children without HIV within different age groups. Both unadjusted incidence rate ratios (uIRRs) and adjusted (aIRRs) are shown, where adjustment was for maternal age at delivery and suburb of residence. Models included child identifier and mother suburb of residence as a random effect. (A) Models include children classified HEU and HUU with high, moderate or low certainty; (B) Models are restricted to children classified HEU or HUU with high or moderate certainty.
| (A) Low, moderate and high certainty children HEU and HUU (N=398,334) | ||||||
|---|---|---|---|---|---|---|
| Age group | Neonatal (days 0 – 27) | Post-neonatal (28 days – 12 months) | (>12 months – 36 months) | |||
| uIRR (95%CI) | aIRR (95%CI) (N=390,779)¥ | uIRR (95%CI) | aIRR (95%CI) (N=387,722) | uIRR (95%CI) | aIRR (95%CI) (N=386,314) | |
| HIV/ART exposure | ||||||
| HUU | Ref | Ref | Ref | Ref | Ref | Ref |
| HEU – ART before pregnancy and start before Universal ART (<2016) | 1.38 (1.10–1.60) | 1.40 (1.21–1.63) | 1.18 (1.11–1.24) | 1.30 (1.22–1.38) | 0.90 (0.83–0.97) | 1.10 (1.02–1.19) |
| HEU – ART before pregnancy and start during Universal ART (≥2016) | 1.34 (0.90–2.00) | 1.35 (0.90–2.02) | 1.17 (1.00–1.38) | 1.23 (1.05–1.44) | 0.79 (0.63–0.98) | 0.91 (0.73–1.14) |
| HEU – ART restart during pregnancy | 1.50 (1.17–1.91) | 1.54 (1.21–1.98) | 1.34 (1.22–1.47) | 1.45 (1.32–1.60) | 0.94 (0.82–1.07) | 1.09 (0.96–1.25) |
| HEU – ART start during pregnancy | 1.41 (1.24–1.60) | 1.44 (1.27–1.63) | 1.06 (1.01–1.11) | 1.13 (1.08–1.19) | 0.78 (0.73–0.83) | 0.91 (0.85–0.97) |
| HEU – no ART during pregnancy† | 1.48 (1.16–1.89) | 1.49 (1.17–1.90) | 1.38 (1.28–1.51) | 1.44 (1.31–1.58) | 0.98 (0.87–1.11) | 1.11 (0.98–1.26) |
| HEU – unknown ART‡ | 1.27 (0.90–1.79) | 1.31 (0.93–1.85) | 1.23 (1.08–1.39) | 1.29 (1.14–1.47) | 0.89 (0.75–1.06) | 1.00 (0.84–1.18) |
| HEU – no ART evidence ever | 1.41 (0.97–2.07) | 1.41 (0.97–2.07) | 0.92 (0.78–1.09) | 0.96 (0.81–1.13) | 0.78 (0.64–0.97) | 0.85 (0.69–1.05) |
| (B) Moderate and high certainty children HEU and HUU (N=62,220) | ||||||
| Age group | Neonatal (days 0 – 27) | Post-neonatal (28 days – 12 months) | (>12 months – 36 months) | |||
| uIRR (95%CI) | aIRR (95%CI) (N=59,233) | uIRR (95%CI) | aIRR (95%CI) (N=59,092) | uIRR (95%CI) | aIRR (95%CI) (N=58,930) | |
| HIV/ART exposure | ||||||
| HUU | Ref | Ref | Ref | Ref | Ref | Ref |
| HEU – ART before pregnancy and start before Universal ART (<2016) | 1.47 (1.14–1.90) | 1.46 (1.13–1.90) | 1.29 (1.18–1.41) | 1.36 (1.24–1.49) | 0.93 (0.84–1.04) | 1.03 (0.91–1.16) |
| HEU – ART before pregnancy and start during Universal ART (≥2016) | 1.23 (0.74–2.04) | 1.24 (0.75–2.07) | 1.19 (1.00–1.41) | 1.20 (1.01–1.43) | 0.76 (0.60–0.96) | 0.80 (0.63–1.02) |
| HEU – ART restart during pregnancy | 1.56 (1.11–2.20) | 1.59 (1.12–2.24) | 1.47 (1.31–1.66) | 1.54 (1.37–1.74) | 0.99 (0.85–1.16) | 1.06 (0.90–1.25) |
| HEU – ART start during pregnancy | 1.50 (1.17–1.91) | 1.50 (1.18–1.93) | 1.23 (1.14–1.34) | 1.26 (1.15–1.38) | 0.88 (0.80–0.98) | 0.94 (0.84–1.05) |
| HEU – no ART during pregnancy† | 1.87 (1.34–2.62) | 1.89 (1.35–2.64) | 1.78 (1.58–2.00) | 1.79 (1.58–2.01) | 1.23 (1.05–1.43) | 1.27 (1.08–1.49) |
| HEU – unknown ART‡ | 1.39 (0.88–2.20) | 1.42 (0.90–2.25) | 1.54 (1.33–1.79) | 1.59 (1.37–1.86) | 1.09 (0.89–1.33) | 1.13 (0.92–1.39) |
| HEU – no ART evidence ever | 1.60 (0.92–2.75) | 1.61 (0.93–2.78) | 1.26 (1.03–1.54) | 1.25 (1.01–1.53) | 1.02 (0.78–1.32) | 1.04 (0.79–1.36) |
As it was not possible to have a repeat admission during the neonatal period, child identifier was not included as a random effect in the neonatal period model.
Maternal ART start date at delivery or postpartum
Maternal ART start before or during pregnancy, but no electronic evidence of ART dispensing during pregnancy
Abbreviations – aIRR: adjusted incidence rate ratio; ART: Antiretroviral therapy; CI: Confidence interval; HEU: exposed to maternal HIV and uninfected; HUU: unexposed to maternal HIV and uninfected; RE: random effects; uIRR: unadjusted incidence rate ratio
Note: Bold indicates IRRs and 95% CIs with intervals excluding 1.
Adjusting for maternal age and mother’s suburb of residence had little impact on estimated IRRs for either the neonatal or post-neonatal periods (Table 4A). In the 12 – 36 months age group, however, these adjustments removed evidence for a reduced rate of hospitalisation in children HEU vs. HUU in all groups except those whose mothers started ART during pregnancy: this association was also attenuated (from 0.78 to 0.91) by adjustment.
When incorporating birthweight in models as a potential mediator, in addition to maternal age and suburb, maternal HIV/ART exposure and infectious-cause hospitalisation remained associated for children HEU whose mothers had ART recorded, compared to children HUU (Table, Supplemental Digital Content 6).
Sensitivity analysis including only children classified HEU or HUU with high or moderate certainty:
Restricting to children HEU and HUU classified with moderate or high certainty, the estimated increases in hospitalisation rate for children HEU whose mothers were not on ART during pregnancy, relative to children HUU, were substantially larger, compared to the main analysis, for all three age groups (e.g. neonatal period: main analysis aIRR=1.49; 95% CI:1.17–1.90 vs. sensitivity analysis aIRR=1.89; 95% CI:1.35–2.64) (Table 4B). During the >12 – 36-month period, there was weak evidence that children HEU whose mothers started ART before pregnancy during the universal ART era had reduced rates of hospitalisation, compared to children HUU (aIRR=0.80; 95% CI:0.63–1.02).
Factors associated with infectious-cause hospitalisation
Factors associated with increased hospitalization rates in univariable (Table, Supplemental Digital Content 7) and multivariable analyses (Table 5), among both children HEU and HUU, were: male sex (all hospitalisation age periods), low/very low/ extremely low birth weight (all hospitalisation age periods), multiple pregnancies (post-neonatal period), parity ≥2 (neonatal period for children HEU and post-neonatal period for children HEU and HUU), and being born in autumn (neonatal and post-neonatal periods). Among children HEU, maternal HIV VL ≥1000 copies/mL during pregnancy was associated with increased hospitalisation rates during the post-neonatal period in univariable and multivariable analyses.
Table 5:
Multivariable Poisson regression models assessing factors associated with infectious-cause hospitalisation in children without HIV within different age groups
| Age group | Neonatal¥ (days 0 – 27) | Post-neonatal (28 days – 12 months) | (>12 months – 36 months) | |||
|---|---|---|---|---|---|---|
| Children HUU aIRR (95%CI) (N=321,544) |
Children HEU aIRR (95%CI) (N=67,150) |
Children HUU aIRR (95%CI) (N=319,070) |
Children HEU aIRR (95%CI) (N=66,618) |
Children HUU aIRR (95%CI) (N=318,245) |
Children HEU aIRR (95%CI) (N=66,046) |
|
| Maternal age at delivery (years) | ||||||
| 15 – 19 | Ref | Ref | Ref | Ref | Ref | Ref |
| 20 – 39 | 0.87 (0.77–0.98) | 0.79 (0.53–1.15) | 0.83 (0.79–0.86) | 0.81 (0.70–0.94) | 0.88 (0.84–0.92) | 0.87 (0.70–1.08) |
| 40 – 50 | 0.61 (0.44–0.83) | 0.90 (0.53–1.51) | 0.76 (0.69–0.84) | 0.89 (0.73–1.10) | 0.80 (0.71–0.91) | 1.20 (0.91–1.59) |
| Child sex: male | 1.24 (1.14–1.34) | 1.29 (1.11–1.50) | 1.41 (1.37–1.45) | 1.45 (1.36–1.54) | 1.25 (1.21–1.29) | 1.27 (1.17–1.38) |
| Birthweight (g) | ||||||
| Normal (2500 – <4000) | Ref | Ref | Ref | Ref | Ref | Ref |
| Fœtal Macrosomia (≥4000) | 1.20 (0.99–1.46) | 1.22 (0.83–1.80) | 0.82 (0.75–0.88) | 0.90 (0.76–1.08) | 0.96 (0.88–1.05) | 0.87 (0.68–1.11) |
| Low (1500 – <2500) | 1.51 (1.35–1.68) | 1.23 (1.00–1.52) | 1.61 (1.55–1.68) | 1.62 (1.50–1.75) | 1.38 (1.32–1.45) | 1.29 (1.15–1.44) |
| Very low (1000 <1500) | 2.68 (2.16–3.33) | 2.28 (1.58–3.30) | 3.88 (3.59–4.19) | 3.10 (2.67–3.59) | 2.21 (1.98–2.47) | 1.92 (1.52–2.42) |
| Extremely low (<1000) | 3.33 (2.44–4.54) | 2.64 (1.41–4.96) | 5.17 (4.59–5.83) | 4.26 (3.29–5.51) | 3.44 (2.92–4.06) | 2.72 (1.82–4.05) |
| Multiple pregnancy | 0.83 (0.65–1.07) | 0.91 (0.61–1.36) | 1.38 (1.27–1.49) | 1.27 (1.10–1.45) | 0.87 (0.77–0.97) | 1.09 (0.88–1.35) |
| Parity | ||||||
| 0 | Ref | Ref | Ref | Ref | Ref | Ref |
| 1 | 1.04 (0.95–1.15) | 1.07 (0.90–1.28) | 1.14 (1.10–1.18) | 1.12 (1.05–1.20) | 1.09 (1.04–1.13) | 1.08 (0.98–1.18) |
| 2 | 1.01 (0.86–1.17) | 1.30 (1.02–1.65) | 1.23 (1.17–1.30) | 1.10 (0.99–1.21) | 1.15 (1.08–1.23) | 1.10 (0.97–1.27) |
| ≥3 | 1.13 (0.90–1.42) | 1.59 (1.10–2.29) | 1.21 (1.11–1.31) | 1.30 (1.11–1.52) | 0.95 (0.85–1.07) | 0.95 (0.74–1.23) |
| Season of birth † | ||||||
| Summer | Ref | Ref | Ref | Ref | Ref | Ref |
| Autumn | 1.53 (1.37–1.72) | 1.36 (1.10–1.67) | 1.06 (1.02–1.11) | 1.05 (0.97–1.14) | 1.01 (0.96–1.06) | 0.87 (0.77–0.98) |
| Winter | 1.26 (1.12–1.42) | 1.00 (0.80–1.24) | 0.82 (0.79–0.86) | 0.92 (0.85–1.00) | 0.97 (0.92–1.02) | 0.89 (0.80–1.00) |
| Spring | 0.96 (0.84–1.08) | 0.87 (0.70–1.09) | 0.81 (0.78–0.84) | 0.86 (0.79–0.93) | 0.98 (0.94–1.03) | 0.92 (0.82–1.03) |
| CD4 cell count during pregnancy | ||||||
| ≥350 cells/μL | – | Ref | – | Ref | – | Ref |
| <350 cells/μL | – | 0.96 (0.81–1.15) | – | 1.07 (0.99–1.14) | – | 0.99 (0.90–1.09) |
| No CD4 cell count record | – | 0.95 (0.77–1.16) | – | 1.05 (0.97–1.14) | – | 1.03 (0.93–1.15) |
| Viral load during pregnancy | ||||||
| <1000 copies/mL | – | Ref | – | Ref | – | Ref |
| ≥1000 copies/mL | – | 1.17 (0.94–1.42) | – | 1.17 (1.08–1.27) | – | 1.05 (0.94–1.18) |
| No VL record | – | 0.99 (0.80 −1.23) | – | 1.04 (0.96–1.13) | – | 0.93 (0.82–1.04) |
| Variance of RE (95% CI): Suburb | 0.06 (0.03 – 0.11) | 0.02 (0.002–0.30) | 0.15 (0.11–0.21) | 0.12 (0.08–0.20) | 0.22 (0.16–0.31) | 0.22 (0.14–0.34) |
| Variance of RE (95% CI): Suburb > Study ID | – | – | 1.58 (1.52–1.65) | 1.47 (1.35–1.59) | 2.16 (2.08–2.24) | 2.29 (2.10–2.50) |
Models were adjusted for year of child birth.
As it was not possible to have a repeat admission during the neonatal period, child identifier was not included as a random effect in the neonatal period models.
Season defined as: Summer (December – February); Autumn (March – May); Winter (June – August); Spring (September – November)[7].
We controlled for season of birth to account for the “Paediatric Surge Season” (Summer and Autumn) in the Western Cape in which there in an increase in hospitalisations due to lower respiratory tract infections and diarrhoea among children.
Abbreviations – aIRR: adjusted incidence rate ratio; ART: antiretroviral therapy; CI: confidence interval; g: grams, HEU: exposed to maternal HIV and uninfected; HUU: unexposed to maternal HIV and uninfected; RE: Random effect; SD: standard deviation
Note: Bold indicates IRRs and 95% CIs with intervals excluding 1.
Discussion
In this provincial birth cohort, there were higher crude infectious-cause hospitalisation rates in the first year of life in children HEU compared to HUU. After the first year of life, crude estimates indicated a reduced risk of hospital admissions in children HEU relative to HUU.
Our finding of increased infectious-cause admission rates in children HEU vs. HUU in the first year of life is consistent with findings of single-facility studies in the WC[7,8,21]. We observed the greatest relative rates of admission among children HEU, (vs. HUU), during the late neonatal period (7 – 27 days of life). Similarly, another WC study reported higher infection-related hospitalisation incidence among children HEU vs. HUU between 8 days and 3 months of life[7].
Stratified by maternal ART start, the admission rates were substantially higher in the first year of life for children HEU whose mothers started ART before pregnancy and prior to Universal ART, started or restarted ART during pregnancy, or were not on ART during pregnancy, compared to those HUU. There was evidence for the magnitude of increased risk being lower in the post-neonatal (relative to neonatal) periods in some groups, particularly for children whose mothers started ART during pregnancy. This highlights the potential role of maternal ART in ameliorating the excess risk of infectious-cause admissions in the post-neonatal period among children HEU. ART start during pregnancy may also be considered a proxy for engagement in antenatal care which is reportedly linked to better engagement in postnatal paediatric care [22,23]. This in turn could play an important role in reducing excess morbidity among HEU children. Increased hospitalisation rates during the neonatal and post-neonatal period in children HEU whose mothers restarted ART during pregnancy or were not on ART during pregnancy highlights the importance of initiating ART and enabling retention on ART.
After age 12 months, there was evidence of reduced hospitalisation risk among children whose mothers initiated ART during pregnancy (and in univariate analysis also among those whose mothers started ART before pregnancy during Universal ART), relative to children HUU. Other studies have reported that the increased risk of infection-related hospitalisation in children HEU wanes with age, with Le Roux et al. reporting the association between HIV exposure and infection-related admissions after 12 months as aIRR=0.71; 95% CI:0.23–2.16[3,7]. One hypothesis is that once the effects of being exposed to HIV and ART wane after the first year of life, the wider benefits of better maternal health and/or healthcare engagement in children of mothers retained on ART are seen. Another consideration is that pulmonary tuberculosis was not included as an infectious event outcome in this study. Moore et al. showed that pulmonary tuberculosis accounts for the highest fraction of pneumonias in children HIV-exposed aged 1–5 years, compared to eighth highest among children HIV-unexposed[24]. The HIV/ART associations with infection-related hospitalisations observed for the 12 – 36-month age period may therefore be under-estimated. There is also potential survival/follow-up bias reducing associations for this period, as a higher proportion of children HEU compared to HUU died in-facility during follow-up (we did not account for out-of-facility deaths in this analysis). Additionally, as we censored follow up for children HEU diagnosed with HIV at the time of their last negative test, the most vulnerable children HEU (i.e. those with characteristics associated with vertical transmission such as high maternal VL) are excluded progressively over time.
When excluding all children with low-certainty HIV exposure and infection status, there was an increase in the estimated relative risk of admission among children HEU in all ART groups except for those whose mothers started ART before pregnancy and during Universal ART, compared to children HUU. The risk appeared particularly high for children HEU whose mothers were not on ART during pregnancy. However, higher certainty of HIV exposure may be associated with being admitted to hospital, as children, and sometimes mothers, are routinely tested for HIV during hospitalisations.
As in other studies, LRTI and diarrhoea were the predominant causes of hospitalisation in this cohort[7,8,21], both of which are known major causes of morbidity and mortality among young children[25]. Morbidity and mortality due to LRTI and diarrhoea can be substantially reduced through optimal breastfeeding and childhood vaccinations; strategies already recommended in current guidelines[25]. Nevertheless, even children HEU who are exclusively breastfed are at increased risk of infectious-cause outcomes compared to children HUU[26].
In this study, higher parity was associated with an increased risk of infection-related admission among children HEU and HUU. As a higher proportion of mothers of children HEU had a parity of ≥1 compared to children HUU, it is possible that parity was driving part of the observed increased risk of hospitalisation in children HEU vs. HUU. Evidence suggests that higher parity could be acting as a proxy for lower SES[27]. Residual confounding may therefore be contributing to the association observed between HIV/ART exposure and infectious-cause admissions in these analyses.
Low birthweight infants have been reported to have an increased risk of morbidity, including hospitalisation[28,29]. In this cohort, it is evident that low birthweight infants are a high-risk group that require closer monitoring beyond age 1 year for both children HEU and HUU. The excess hospitalisation risk among low/very low/extremely low, compared to normal birthweight children was higher for children HUU than HEU, indicating that low birthweight may be more of a driving factor for infectious-cause hospitalisation among children HUU in the absence of the effects of HIV and ART exposure. The elevated risk of infectious disease hospitalisation associated with low birthweight, autumn birth and HIV exposure especially in the first 6 months of life suggests that interventions like respiratory syncytial virus immunisation as recommended by WHO could mitigate some of this burden[30]. The association between elevated maternal VL during pregnancy and infection-related hospitalisations, among children HEU, during the post-neonatal period, is similar to findings from other studies[7,21].
Strengths and limitations:
This analysis provides the largest population level assessment of infectious-cause outcomes in children HEU relative to HUU to date. Moreover, we were able to analyse the effect of HIV exposure through a period of improved access to maternal pre-pregnancy ART (Universal ART for all people living with HIV).
This analysis was restricted to variables that are routinely collected in maternal and child care and/or available within the WCPHDC. Reliable breastfeeding, gestational age, and vaccination data, all of which have been reported to be important factors associated with infectious-cause outcomes among children HEU[7,8,21], were not available within the WCPHDC at the time of this study and we were unable to assess their impact on the results observed. We were also unable to adjust for other potential confounders such as maternal education and substance use. Therefore, estimates from this study should not be interpreted as causal.
Furthermore, we were unable to account for children relocating into and out of the WC and out-of-hospital deaths, all of which may be differential by HIV exposure and ART status, and may therefore have underestimated hospitalisations, deaths, and the associations between HIV/ART exposure and hospitalisation. The classification of ART exposure is also subject to ascertainment bias. Mothers for whom there is no electronic record of ART dispensing, and their children, may be accessing healthcare in the private sector, may have relocated to another province, or may be deceased. Additionally, due to the lack of gestational age data, pregnancy start date was estimated as 42 weeks before child date of birth. There are, however, children that would have been born preterm, resulting in some misclassification of timing of ART start relative to pregnancy.
As only four types of infections were considered for hospital admissions, many other neonatal infections were excluded (e.g. sepsis, necrotising enterocolitis, and congenital infections). It is therefore possible that the relative risk of admission, among children HEU vs. HUU, during the neonatal period is underestimated.
Conclusions:
This large population-level cohort illustrates that, even with greater access to maternal and pre-pregnancy ART, children HEU vs. HUU were at increased risk of infection-related hospitalisation, particularly during the neonatal period. Given the large population of children HEU in SA and globally, this places additional burdens on already strained healthcare systems. Children HEU with intermittent/less ART exposure (whose mothers restarted ART during pregnancy after a gap) or were not on ART during pregnancy had the highest risk of hospitalisation relative to children HUU. In addition to interventions to support maternal ART initiation and adherence, it’s important to consider the household, environmental, community and societal factors associated with being a child affected by HIV[13], as well as sustained engagement in care of both mothers and children.
Supplementary Material
Acknowledgements:
Kathleen Kehoe and Erna Modern contributed to the curation and management of the data.
Conflict of interest and sources of funding:
KA, EK, AB, and MAD, receive funding from ViiV Healthcare for an unrelated project. ALS has been permanently employed by Elsevier for The Lancet Child and Adolescent Health since April 2023.
This work was supported by the University of Bristol’s Pro Vice-Chancellor Research and Enterprise Strategic Research Fund and the Global Challenge Research Fund Strategy funded by Research England, (to STdB); by the National Institute of Health Fogarty International Centre grant (K43TW010683 to ALS); by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health CHERISH study (R61HD103093 to ALS and MAD with support for FP and AB); by the Western Cape Department of Health (to WCPHDC); by the US National Institutes for Health (R01 HD080465 and U01 AI069924 to WCPHDC); and the Bill and Melinda Gates Foundation (1164272 and 1191327 to WCPHDC).
Footnotes
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
References
- 1.Slogrove AL, Powis KM, Johnson LF, Stover J, Mahy M. Estimates of the global population of children who are HIV-exposed and uninfected, 2000–18: a modelling study. Lancet Glob Health 2020; 8:e67–e75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Slogrove A, Reikie B, Naidoo S, De Beer C, Ho K, Cotton M, et al. HIV-Exposed Uninfected Infants are at Increased Risk for Severe Infections in the First Year of Life. J Trop Pediatr 2012; 58:505–508. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Slogrove AL, Goetghebuer T, Cotton MF, Singer J, Bettinger JA. Pattern of infectious morbidity in HIV-exposed uninfected infants and children. Front Immunol 2016; 7:1–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.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. Clinical Infectious Diseases 2019; 68:1193–1203. [DOI] [PubMed] [Google Scholar]
- 5.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:e92–107. [DOI] [PubMed] [Google Scholar]
- 6.von Mollendorf C, von Gottberg A, Tempia S, Meiring S, de Gouveia L, Quan V, et al. Increased risk for and mortality from invasive pneumococcal disease in HIV-exposed but uninfected infants aged <1 year in South Africa, 2009–2013. Clinical infectious diseases 2015; 60:1346–1356. [DOI] [PubMed] [Google Scholar]
- 7.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; 4:220–231. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Anderson K, Kalk E, Madlala HP, Nyemba DC, Kassanjee R, Jacob N, et al. Increased infectious-cause hospitalization among infants who are HIV-exposed uninfected compared to HIV-unexposed. AIDS 2021; 35:1–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Anderson K, Kalk E, Madlala HP, Nyemba DC, Jacob N, Slogrove A, et al. Preterm birth and severe morbidity in hospitalized neonates who are HIV exposed and uninfected compared with HIV unexposed. AIDS 2021; 35:921–931. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Slogrove AL, Esser MM, Cotton MF, Speert DP, Kollmann TR, Singer J, et al. A Prospective Cohort Study of Common Childhood Infections in South African HIV-exposed Uninfected and HIV-unexposed Infants. Pediatric Infectious Disease Journal 2017; 36:e38–e44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Naidoo K, Singh J, Lalloo U. Critical analysis of ICU/HC beds in South Africa: 2008–2009. South African Medical Journal 2013; 103:751–753. [DOI] [PubMed] [Google Scholar]
- 12.Argent AC, Ranjit S, Peters MJ, Andre-von Arnim A von Saint, Chisti MJ, Jabornisky R, et al. Factors to be Considered in Advancing Pediatric Critical Care Across the World. Crit Care Clin 2022; 38:707–720. [DOI] [PubMed] [Google Scholar]
- 13.Ramokolo V, Goga AE, Slogrove AL, Powis KM. Unmasking the vulnerabilities of uninfected children exposed to HIV. The BMJ 2019; 366:1–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Boulle A, Heekes A, Tiffin N, Smith M, Mutemaringa T, Zinyakatira N, et al. Data Centre Profile : The Provincial Health Data Centre of the Western Cape Province, South Africa. Int J Popul Data Sci 2019; 4:06. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Department of Statistics South Africa. Census 2022. 2024.https://census.statssa.gov.za/#/province/1/2 (accessed 25 Jan 2024).
- 16.Kufa-Chakesha T, Shangase N, Lombard C, Manda S, Puren A. The 2022 Antenatal HIV Sentinel Survey Key Findings; 2024. https://www.nicd.ac.za/wp-content/uploads/2024/01/Antenatal-survey-2022-report_National_Provincial_12Jul2023_Clean_01.pdf (accessed 29 Jan 2024).
- 17.Slogrove AL, Burmen B, Davies M-A, Edmonds A, Abrams EJ, Chadwick EG, et al. Standardized Definitions of In Utero Human Immunodeficiency Virus and Antiretroviral Drug Exposure Among Children. Clinical Infectious Diseases 2022; 75:347–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.de Beer ST, Davies M-A, Phelanyane F, Jones HE, Ingle SM, Eley BS, et al. The Retrospective Implementation of Standardized In Utero HIV Exposure Definitions Using Routinely Collected Public Sector Data Across the Western Cape Province, South Africa. Pediatr Infect Dis J 2024; 43:1061–1064. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Kehoe K, Morden E, Jacobs T, Zinyakatira N, Smith M, Heekes A, et al. Comparison of paediatric infectious disease deaths in public sector health facilities using different data sources in the Western Cape, South Africa (2007–2021). BMC Infect Dis 2023; 23:104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.StataCorp. Stata Statistical Software: Release 17. 2021.
- 21.Wedderburn CJ, Bondar J, Lake MT, Nhapi R, Barnett W, Nicol MP, et al. Risk and rates of hospitalisation in young children: a prospective study of a South African birth cohort. PlOS Glob Public Health 2024; 4:e0002754. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Ndwandwe D, Nnaji CA, Mashunye T, Uthman OA, Wiysonge CS. Incomplete vaccination and associated factors among children aged 12–23 months in South Africa: an analysis of the South African demographic and health survey 2016. Hum Vaccin Immunother 2021; 17:247–254. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Nelson AK, Cassidy T, Duran LT, Cox V, Wedderburn CJ, Giddy J, et al. An analysis of the HIV testing cascade of a group of HIV-exposed infants from birth to 18 months in peri-urban Khayelitsha, South Africa. PLoS One 2022; 17:e0262518. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Moore DP, Baillie VL, Mudau A, Wadula J, Adams T, Mangera S, et al. The Etiology of Pneumonia in HIV-uninfected South African Children: Findings from the Pneumonia Etiology Research for Child Health (PERCH) Study. Pediatric Infectious Disease Journal 2021; 40:S59–S68. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.World Health Organization. Ending Preventable Child Deaths from Pneumonia and Diarrhoea by 2025 - The integrated Global Action Plan for Pneumonia and Diarrhoea (GAPPD); 2013. [DOI] [PubMed]
- 26.Verani JR, Groome MJ, Zar HJ, Zell ER, Kapongo CN, Nzenze SA, et al. Risk Factors for Presumed Bacterial Pneumonia among HIV-uninfected Children Hospitalized in Soweto, South Africa. Pediatric Infectious Disease Journal 2016; 35:1169–1174. [DOI] [PubMed] [Google Scholar]
- 27.Kozuki N, Lee AC, Silveira MF, Sania A, Vogel JP, Adair L, et al. The associations of parity and maternal age with small-for-gestational-age, preterm, and neonatal and infant mortality: A meta-analysis. BMC Public Health 2013; 13:S2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Hviid A, Melbye M. The Impact of Birth Weight on Infectious Disease Hospitalization in Childhood. Am J Epidemiol 2007; 165:756–761. [DOI] [PubMed] [Google Scholar]
- 29.Rüdiger M, Heinrich L, Arnold K, Druschke D, Reichert J, Schmitt J. Impact of birthweight on health-care utilization during early childhood – a birth cohort study. BMC Pediatr 2019; 19:1–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.World Health Organization. Respiratory Syncytial Virus (RSV). 2025.https://www.who.int/teams/immunization-vaccines-and-biologicals/diseases/respiratory-syncytial-virus-(rsv) (accessed 25 Jul 2025).
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