Integrated growth assessment in the first 1000 d of life: an interdisciplinary conceptual framework.

OBJECTIVES: Prenatal growth affects short- and long-term morbidity, mortality and growth, yet communication between prenatal and postnatal healthcare teams is often minimal. This paper aims to develop an integrated, interdisciplinary framework for foetal/infant growth assessment, contributing to the continuity of care across the first 1000 d of life. DESIGN: A multidisciplinary think-tank met regularly over many months to share and debate their practice and research experience related to foetal/infant growth assessment. Participants' personal practice and knowledge were verified against and supplemented by published research. SETTING: Online and in-person brainstorming sessions of growth assessment practices that are feasible and valuable in resource-limited, low- and middle-income country (LMIC) settings. PARTICIPANTS: A group of obstetricians, paediatricians, dietitians/nutritionists and a statistician. RESULTS: Numerous measurements, indices and indicators were identified for growth assessment in the first 1000 d. Relationships between foetal, neonatal and infant measurements were elucidated and integrated into an interdisciplinary framework. Practices relevant to LMIC were then highlighted: antenatal Doppler screening, comprehensive and accurate birth anthropometry (including proportionality of weight, length and head circumference), placenta weighing and incorporation of length-for-age, weight-for-length and mid-upper arm circumference in routine growth monitoring. The need for appropriate, standardised clinical records and corresponding policies to guide clinical practice and facilitate interdisciplinary communication over time became apparent. CONCLUSIONS: Clearer communication between prenatal, perinatal and postnatal health care providers, within the framework of a common understanding of growth assessment and a supportive policy environment, is a prerequisite to continuity of care and optimal health and development outcomes.

Comparison of Feeding Practices and Growth of Urbanized African Infants Aged 6-12 Months Old by Maternal HIV Status in Gauteng Province, South Africa.

Appropriate feeding practices are protective against malnutrition and poor growth. We compared feeding practices and growth in HIV-exposed-uninfected (HEU) and HIV-unexposed-uninfected (HUU) between 6-12 months of age in urbanized African infants in South Africa. A repeated cross-sectional analysis was used to determine differences in infant feeding practices and anthropometric measures by HIV exposure status at 6, 9, and 12 months in the Siyakhula study. The study included 181 infants (86 HEU; 95 HUU). Breastfeeding rates were lower in HEU vs. HUU infants at 9 (35.6% vs. 57.3%; p = 0.013) and 12 months (24.7% vs. 48.0%; p = 0.005). Introduction to early complementary foods was common (HEU = 16.2 ± 11.0 vs. HUU = 12.8 ± 9.3 weeks; p = 0.118). Lower weight-for-age Z-scores (WAZ) and head circumference-for-age Z-scores (HCZ) were found in HEU infants at birth. At 6 months, WAZ, length-for-age Z-scores (LAZ), HCZ, and mid-upper-arm circumference-for-age Z-scores (MUACAZ) were lower in HEU vs. HUU infants. At 9 months, lower WAZ, LAZ, and MUACAZ were found in HEU vs. HUU infants. At 12 months, lower WAZ, MUACAZ, and weight-for-length Z-scores (-0.2 ± 1.2 vs. 0.2 ± 1.2; p = 0.020) were observed. HEU infants had lower rates of breastfeeding and poorer growth compared to HUU infants. Maternal HIV exposure affects the feeding practices and growth of infants.

Association of Prenatal Placental Function with Anthropometry and Body Composition through 2 years of Age in South African Infants: The UmbiBaby Study.

BACKGROUND: Placental insufficiency negatively impacts fetal growth and body composition (BC), potentially affecting lifelong health. Placental insufficiency, detectable as an abnormal umbilical artery resistance index (UmA-RI) on Doppler ultrasonography, is highly prevalent in otherwise healthy South African pregnant women. Appropriate intervention reduces stillbirth and perinatal death, but research on long-term outcomes of surviving infants is lacking. OBJECTIVES: This study aimed to describe and compare anthropometry and BC during the first 2 y of life in a cohort of term-born infants with normal and abnormal prenatal UmA-RI. METHODS: Term-born infants (n = 81; n = 55 normal, n = 26 abnormal UmA-RI on third trimester Doppler screening) were followed up at 8-time points until age 2 y. Anthropometric measurements were taken, and FFM and FM were assessed by deuterium dilution. Age- and sex-specific z-scores were calculated for anthropometric indices, FM, FFM, FM index (FMI), and FFM index (FFMI) using appropriate reference data. Anthropometry and BC of infants with normal and abnormal UmA-RI were compared using an independent t-test or Mann-Whitney test. RESULTS: At most ages, group mean z-scores were <0 for length-for-age and FM and >0 for weight-for-length and FFM. Compared with infants with normal UmA-RI, infants with abnormal UmA-RI had significantly lower weight-for-age z-scores at birth (-0.77 ± 0.75 compared with -0.30 ± 1.10, P = 0.026), ages 10 wk to 9 mo (-0.4 ± 0.87 to -0.2 ± 1.12 compared with 0.3 ± 0.85 to 0.6 ± 1.09; P = 0.007-0.017) and 18 mo (-0.6 ± 0.82 compared with 0.1 ± 1.18; P = 0.037); length-for-age z-scores at ages ≤14 wk (-1.3 ± 1.25 to -0.9 ± 0.87 compared with -0.2 ± 1.04 to -0.1 ± 1.00; P = 0.004-0.021); and FFM-for-age z-scores at ages ≤9 mo (-0.1 ± 0.82 to 0.7 ± 0.71 compared with 0.7 ± 1.00 to 1.3 ± 0.85; P = 0.002-0.028). FFMI, percentage FFM, FM, percentage FM, and FMI showed no consistent significant differences. CONCLUSIONS: Infants with abnormal UmA-RI had lower weight-for-age and length-for-age z-scores, particularly at younger ages, with proportionally lower FFM but no consistent differences in percentage FFM and FFMI. These findings merit further investigation in larger cohorts.

Early Childhood Growth Parameters in South African Children with Exposure to Maternal HIV Infection and Placental Insufficiency.

Maternal HIV exposure and intrauterine growth restriction (IUGR) due to placental insufficiency both carry major risks to early child growth. We compared the growth outcomes of children aged 18 months who had abnormal umbilical artery resistance indices (UmA-RI), as a marker of placental insufficiency, with a comparator group of children with normal UmA-RI during pregnancy, as mediated by maternal HIV infection. The cross-sectional study included 271 children, grouped into four subgroups based on HIV exposure and history of normal/abnormal UmA-RI, using available pregnancy and birth information. Standard procedures were followed to collect anthropometric data, and z-scores computed as per World Health Organization growth standards. Lower length-for-age z-scores (LAZ) were observed in children who were HIV-exposed-uninfected (CHEU) (-0.71 ± 1.23; p = 0.004) and who had abnormal UmA-RI findings (-0.68 ± 1.53; p < 0.001). CHEU with abnormal UmA-RI had lower LAZ (-1.3 ± 1.3; p < 0.001) and weight-for-age z-scores (WAZ) (-0.64 ± 0.92; p = 0.014) compared to the control group. The prevalence of stunting was 40.0% in CHEU with abnormal UmA-RI and 16.0% in CHEU with normal UmA-RI (p < 0.001; p = 0.016, respectively). In conclusion, maternal HIV exposure and placental insufficiency are independent risk factors for childhood stunting, with this risk potentiated when these two risk factors overlap.

Identifying the High-Risk Fetus in the Low-Risk Mother Using Fetal Doppler Screening.

Identifying the high-risk fetus in the low-risk pregnant mother (LRM) is a neglected area of research. Fetal growth restriction (FGR) is a major cause of stillbirths, especially in low- and middle-income countries (LMICs). FGR is very poorly detected particularly in healthy pregnant women classified as low risk. Umbiflow is an inexpensive continuous-wave Doppler ultrasound (CWDU) apparatus that is suitable for use by low-level health care providers for screening low-risk pregnant populations. It can easily detect umbilical artery blood flow in the cord, which correlates well with placental function, and poor placental function correlates well with FGR.Use of CWDU to screen an LMIC population of more than 7,000 LRMs has demonstrated a high prevalence of abnormal umbilical artery flow of 13%, and absent end-diastolic flow, which is associated with end-stage placental disease, was found in 1.2%. This is 10 times higher than previously reported in high-income countries. Screening with CWDU together with a standard protocol managing those pregnancies with abnormal placental blood flow resulted in a 43% reduction in stillbirths (risk ratio: 0.57; 95% confidence interval=0.29, 0.85) in this LRM population. Further, follow-up of infants who had abnormal umbilical artery blood flow showed that these infants had significantly less fat-free mass at ages 6 weeks, 10 weeks, 14 weeks, and 6 months, than those with normal umbilical artery blood flow (P<.015), confirming that CWDU was able to detect true FGR.Thus, screening with CWDU can detect the fetus at risk of stillbirth, and infants likely to have suboptimal growth and development postnatally. Screening with CWDU in LRMs opens the door to a step change in preventing stillbirths in LMICs.

Cotrimoxazole guidelines for infants who are HIV-exposed but uninfected: a call for a public health and ethics approach to the evidence.

WHO first recommended cotrimoxazole prophylaxis for all infants who are HIV-exposed but uninfected (HEU) in 2000, given the ability of this treatment to prevent mortality from pneumocystis pneumonia in adults living with HIV. Over the last 21 years, evidence has been generated from the use of cotrimoxazole prophylaxis in infants who are HEU, including two randomised controlled trials, which have shown no clinical benefit and an increase in antibiotic resistance and microbiome dysbiosis. Additionally, improvements in health care over the last two decades in terms of antiretroviral treatment and prophylaxis for mothers and infants, and notably improved vaccination programmes, have substantially reduced the risk of HIV transmission and the overall morbidity and mortality of infants who are HEU from pneumonia and diarrhoeal diseases. Here, we highlight these changes in health care alongside the unchanged cotrimoxazole prophylaxis guidelines and call for a change in these guidelines on the basis of a public health and ethics approach.

The ability of continuous-wave Doppler ultrasound to detect fetal growth restriction.

BACKGROUND: Fetal growth restriction (FGR), defined as a fetus failing to reach its genetic growth potential, remains poorly diagnosed antenatally. This study aimed to assess the ability of continuous-wave Doppler ultrasound of the umbilical artery (CWD-UmA) to detect FGR in healthy women with low-risk pregnancies. METHODS AND FINDINGS: This prospective longitudinal descriptive cohort study enrolled infants born to low-risk mothers who were screened with CWD-UmA between 28-34 weeks' gestation; the resistance index (RI) was classified as normal or abnormal. Infants were assessed at 6, 10, 14 weeks, and 6 months postnatally for anthropometric indicators and body composition using the deuterium dilution method to assess fat-free mass (FFM). Neonates in the abnormal RI group were compared with those in the normal RI group, and neonates classified as small-for-gestational age (SGA) were compared with appropriate-for-gestational age (AGA) neonates. Eighty-one term infants were included. Only 6 of 26 infants (23.1%) with an abnormal RI value would have been classified as SGA. The abnormal RI group had significantly reduced mean FFM and FFM-for-age Z-scores at 6, 10, 14 weeks, and 6 months compared with the normal RI group (P<0.015). The SGA group's FFM did not show this consistent trend when compared to AGA FFM, being significantly different only at 6 months (P = 0.039). The main limitation of the study was the small sample size of the infant follow-up. CONCLUSIONS: Abnormal RI obtained from CWD-UmA is able to detect FGR and is considered a useful addition to classifying the neonate only by SGA or AGA at birth.

Is exclusive breastfeeding an option or a necessity in Africa? A pooled study using the deuterium oxide dose-to-mother technique.

Given the valuable health, development, and economic benefits of human milk Exclusive Breastfeeding (EBF) is recommended by the World Health Organisation for the first six months of an infant's life. Many resource-limited regions in Africa do not line-up with these recommendations, therefore EBF promotion efforts on the continent need to be scaled up and monitored. This study explores the human milk intake volumes of 5 countries (Benin, Central African Republic, Morocco, South Africa and Tanzania) both at country level and in a pooled sample of children at 3 months (n= 355) and at 6 months (n=193). Mean human milk intake volumes in the pooled samples were 697.6 g/day at 3 months and 714.9 g/day at 6 months. EBF was determined both by maternal recall as well as using the deuterium oxide dose-to-mother technique, using two different cut-offs of non-milk oral intake. Comparison of these results showed substantial over-reporting of EBF by maternal recall, which suggests that actual rates of EBF are even lower than reported, thus highlighting the importance of scaling-up EBF promotion strategies.

Effect of co-trimoxazole prophylaxis on morbidity and mortality of HIV-exposed, HIV-uninfected infants in South Africa: a randomised controlled, non-inferiority trial.

BACKGROUND: WHO guidelines recommend co-trimoxazole prophylaxis for HIV-exposed, HIV-uninfected infants. These guidelines date back to an era in which HIV testing of infants was impossible and mothers had poor access to antiretroviral treatment. To determine whether this guideline requires revision in the current era of effective prevention of mother-to-child transmission and early infant diagnosis programmes, we aimed to investigate whether receiving no co-trimoxazole prophylaxis is inferior to receiving co-trimoxazole prophylaxis in the resulting incidence of grade 3 or 4 common childhood illnesses or mortality in breastfed HIV-exposed, HIV-uninfected infants. METHODS: We investigated our aim in a randomised controlled, non-inferiority trial. We enrolled the HIV-negative infants of mothers living with HIV who were actively involved in transmission prevention programmes in two clinics in Durban, South Africa. Infants were included in the study if they were breastfeeding at the screening and enrolment visits, and their mother was planning to breastfeed for at least 6 months; were a singleton birth and had a birthweight of 2 kg or more; had no clinically observed genetic disorders; and had no serious illnesses and had not received antibiotics or traditional medications (such as herbal remedies). Infants were randomly assigned (1:1) to receive co-trimoxazole or no co-trimoxazole. In the co-trimoxazole group, infants received the drug until all exposure to HIV had ceased (ie, 6 weeks after last exposure to breastmilk) and the infant was confirmed to be uninfected with HIV. The drug was administered by mothers in once-daily regimens of 20 mg trimethoprim and 100 mg sulfamethoxazole orally (age <6 months or bodyweight <5 kg), or 40 mg trimethoprim and 200 mg sulfamethoxazole orally (age >6 months or bodyweight >5 kg). Clinical and laboratory staff always remained masked to group assignment, but mothers and study counsellors were not. Infants and their mothers attended study visits at ages 6 weeks (for enrolment and randomisation), 10 weeks, 14 weeks, and then monthly from 4 to 12 months. Our primary outcome was the incidence of grade 3 or 4 common childhood illnesses (pneumonia or diarrhoea) or mortality in breastfed HIV-exposed, HIV-uninfected infants by age 12 months. A non-inferiority bound of 5% was used. The study is registered with the Pan African Clinical Trials Registry, number PACTR201311000621110, and the South African National Clinical Trials Registry, number DOH-27-0614-4728. FINDINGS: We screened 1570 mother-child pairs for study enrolment, from whom (78%) eligible infants were enrolled into the study between Oct 16, 2013, and May 23, 2018. Of the infants enrolled, 611 (50%) were randomly assigned to the co-trimoxazole group and 609 (50%) were randomly assigned to the no co-trimoxazole group. One (<1%) infant in the no co-trimoxazole group was excluded from the analysis of the final outcomes for having received traditional medicine (which only became apparent after randomisation); therefore, 611 (50%) infants in the co-trimoxazole group and 608 (50%) infants in the no co-trimoxazole group were included in the final intention-to-treat analysis. 136 (22%) infants in the co-trimoxazole group and 139 (23%) infants in the no co-trimoxazole group did not complete the 12-month study visit, predominantly because of loss to follow-up (93 [15%] infants in the co-trimoxazole group; 90 [15%] infants in the no co-trimoxazole group). The cumulative probability of the composite primary outcome was 0·114 (95% CI 0·076 to 0·147; 49 events) in the co-trimoxazole group versus 0·0795 (0·044 to 0·115; 39 events) in the no co-trimoxazole group. The risk difference (no co-trimoxazole group minus co-trimoxazole group) was -0·0319 (-0·075 to 0·011), meaning that the risk was around 3 percentage points lower in the no co-trimoxazole group on the additive scale. INTERPRETATION: We can conclude that no co-trimoxazole is not inferior to daily co-trimoxazole among breastfed HIV-exposed, HIV-uninfected infants whose mothers are accessing a prevention of mother-to-child transmission programme in an area unaffected by malaria. We therefore believe that WHO should revise the co-trimoxazole guidelines for HIV-exposed, HIV-uninfected infants in areas unaffected by malaria. FUNDING: HIV Prevention Research Unit of the South African Medical Research Council and the Family Larsson-Rosenquist Foundation.

Limitations of maternal recall for measuring exclusive breastfeeding rates in South African mothers.

BACKGROUND: Maternal recall is most commonly used to determine exclusive breastfeeding rates. A gold standard stable isotope method is available which can determine intake of breast milk versus water from sources other than breast milk and thus objectively determine exclusive breastfeeding. The objectives of this study were to determine exclusive breastfeeding rates by both maternal recall and the objective stable isotope method and discuss the limitations and usefulness of the two methods. METHODS: The study involved 100 mother-infant pairs in a peri-urban area in Durban, South Africa and study visits took place from July 2012 to September 2014. Maternal recall of exclusive breastfeeding was carried out using the World Health Organization's 24 hour recall of infant feeding and this was compared to the objective measurement of exclusive breastfeeding using the stable isotope technique at three time points: six weeks, three and 5.5 months. The objective measurements were carried out using two different cut off values for exclusive breastfeeding. Kappa analysis was used to quantify the relationship between maternal recall and results from the stable isotope technique for each mother-infant pair. RESULTS: Over reporting of exclusive breastfeeding was common at the three different time points regardless of the cut off value used to assess exclusive breastfeeding by the stable isotope technique. Kappa analysis also revealed only slight or fair agreement (K < 0.24) between reported and measured exclusive breastfeeding at all time points. CONCLUSIONS: Maternal recall of exclusive breastfeeding is limited in accuracy and should be restricted to large scale epidemiological surveys. The more objective gold standard stable isotope method for measuring intake volumes of breast milk should be used to evaluate interventions with smaller representative samples.

Association of 6 months of exclusive breastfeeding with higher fat-free mass in infants in a low-resource setting with high HIV prevalence in South Africa.

Exclusive breastfeeding for 6 months is recommended by the World Health Organisation (WHO) for optimal health and growth of infants, but it is not a common practice in South Africa. A breastfeeding counselling programme was run to inform, encourage and support mothers to exclusively breastfeed their infants for 6 months, and mother-infant pairs were invited to participate in a research project to determine breast milk intake volumes using the dose-to-mother deuterium dilution stable isotope technique. This technique yields objective measurements of breast milk intake volumes and also enables determination of exclusivity of breastfeeding, which is most frequently determined by maternal recall and can be subject to bias. Exclusivity of breastfeeding at 6 weeks, 3 months and 6 months following birth of the infants was correlated with infant fat-free mass at 12 months, which was determined by the dose-to-infant deuterium dilution stable isotope technique. Results showed that infants who were exclusively breastfed for 6 months had a higher per cent fat-free mass at 12 months compared with infants who were not exclusively breastfed for 6 months (P < 0.05). This objective determination of both breastfeeding patterns and infant body composition gives weight to the WHO recommendation of exclusive breastfeeding for 6 months as it demonstrated adequate fat-free mass in infants at 12 months, even in an area with high HIV prevalence. © 2016 John Wiley & Sons Ltd.

Breastmilk Output in a Disadvantaged Community with High HIV Prevalence as Determined by the Deuterium Oxide Dose-to-Mother Technique.

INTRODUCTION: World Health Organization breastfeeding guidelines for HIV-infected mothers are exclusive breastfeeding for 6 months and then continued breastfeeding for 12 months, provided the mother is receiving antiretroviral prophylaxis. Many African women perceive that breastmilk alone is not sufficient for their infant's nutritional requirements for the first 6 months of life, and mixed feeding is a common practice. METHODOLOGY: A stable isotope technique was used to determine breastmilk output volumes and maternal body composition objectively at five different time points in the first year of the infant's life. RESULTS: Breastmilk output volumes were high for HIV-infected mothers: 831 ± 185 g/day at 6 weeks; 899 ± 188 g/day at 3 months; 871 ± 293 g/day at 6 months; 679 ± 281 g/day at 9 months; and 755 ± 287 g/day at 12 months. These high output volumes had no negative impact on the mother's fat-free mass. The breastmilk output volumes for HIV-uninfected mothers were not significantly different to the outputs for HIV-infected mothers at any of the time points (p > 0.05): 948 ± 223 g/day at 6 weeks; 925 ± 227 g/day at 3 months; 902 ± 286 g/day at 6 months; 746 ± 263 g/day at 9 months; and 713 ± 264 g/day at 12 months. CONCLUSION: This study using objective methodology shows that breastmilk outputs of HIV-infected mothers were relatively high (and within published reference ranges), and mothers are able to provide sufficient breastmilk for their infants without compromising their own fat-free mass.

Increased Exclusivity of Breastfeeding Associated with Reduced Gut Inflammation in Infants.

INTRODUCTION: The development of the intestinal gut is largely influenced by early nutrition. Infant immunity is challenged by the exposure of the gut to foreign bodies, which mediate inflammation of the gut. This study assessed the levels of gut inflammation in relation to the percentage of breastmilk consumed/the exclusivity of breastfeeding in South African infants. This is the first study to examine markers of gut inflammation in infants in relation to exclusivity of breastfeeding measured by a gold standard method. METHODOLOGY: Twenty-four black South African infants were included in this study. The categorization of different degrees of exclusivity of breastfeeding was made using an objective gold standard method developed by the International Atomic Energy Agency (deuterium dilution method). Markers of gut inflammation were measured noninvasively by sampling stool from the infants averaging 6 months of age. Gut inflammation was investigated by running multiple Droplet Digital™ (Bio-Rad, Hercules, CA) polymerization chain reaction tests profiling a panel of five mRNA probes (interleukin-8 [IL-8], S100 calcium-binding protein A8 [S100A8], Toll-like receptor-4, human leukocyte antigen on chromosome 6 region 6p21.31, and defensin alpha 8). These mRNA biomarkers expressions were tested in proportion to number of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) copies as GAPDH is constitutively expressed in most cells. RESULTS: Two previously described robust mRNA markers of gut inflammation (S100A8 and IL-8) were found to correlate significantly to the percentage of breastmilk intake (r(2) = 0.4302, p = 0.0004 and r(2) = 0.3633, p = 0.002, respectively) in the range of 75-100% in 22 samples analyzed. CONCLUSIONS: This study using objective methodology has shown that higher percentages of breastmilk intake are associated with significantly lower levels of gut inflammation. This further supports the health benefits observed in exclusively breastfed infants.