LAZ – Length-for-age Z score; LBW – Low birth weight; LMIC -Low- and middle-income countries; MUAC – Mid-upper arm circumference; NBW – Normal birth weight; SAM – Severe acute malnutrition; u6m – Under 6 months; WLZ – Weight-for-length Z score; WAZ – Weight-for-age Z score; MAMI – Management of At risk Mothers and Infants

Infancy is the period of fastest relative growth; on average, a normally growing infant more than doubles their birth weight in the first six months of life :The WHO Child Growth Standards 2006: [Available from: http://www.who.int/childgrowth/standards/en/]. In early infancy, apparent wasting or underweight may occur due to growth faltering and/or as a result of having been born preterm, low birth weight (LBW) or small for gestational age ¹ .

The global prevalence of LBW is 15%, representing more than 20 million infants, 91% of whom are in low and middle-income countries (LMICs) ² . In LMICs, birthweight and subsequent anthropometry in infancy and childhood are predictive of both short and longer-term mortality ³ . Studies report ongoing extra-uterine weight and length restriction and reduced physical strength through to adolescence following LBW compared to normal birth weight (NBW) infants ⁴ . The rate of infant growth irrespective of birth weight is influenced by nutritional intake, absorption and assimilation of nutrients, nutrient losses due to infection, other acute or chronic diseases, and genetic or epigenetic predisposition ⁵ .

High-quality growth references standards exist for preterm infants from the INTERGROWTH-21 ^st study ⁶ . However, information on gestational age is often unavailable or unreliable in LMICs, hence WHO growth standards are usually applied to all infants irrespective of birth size. In growth monitoring or nutrition programs, LBW babies may be classified as underweight or wasted whilst having a normal (preterm) growth velocity tracking lower percentiles or ‘catching up’. Anthropometric indicators such as weight-for-length Z score (WLZ) and mid-upper arm circumference (MUAC) identify a large proportion of infants with a history of LBW. For example, in Kenya, 43% of ill hospitalized malnourished infants under six months old had a history of small size at birth ¹ , while in India, LBW was a strong predictor of severe wasting among infants below the age of six months ⁷ .

Thus, there is uncertainty among health workers regarding interpretation of anthropometry in LBW infants, with low expectations of growth in LBW infants common and “slow” and potentially “poor” growth in infants (underweight) regarded as acceptable ⁸ . Additionally, practitioners target catch up growth of LBW infants to that of peers and assume that mortality risk is resolved among LBW infants who are no longer classified as undernourished ⁹ . There are also concerns for potential future health risks associated with accelerated weight gain ^{10, 11} . Whether and how to intervene on undernourished LBW infants has implications for health system workload and costs. Consequently, to evaluate risks associated with anthropometry and types of interventions needed, birthweight may need to be considered during anthropometric assessment in infancy. In practice, vaccination at around two months of age is an established opportunity to assess growth and to intervene.

Given this background, we examined data from a birth cohort to compare the discriminatory value for mortality for anthropometry at birth and changes from birth to the following timepoints in infancy: i) at two months of age which is around the time of infant immunisations; and ii) at six months of age. We also investigated overall mortality risk among LBW infants and whether among infants with low anthropometric values measured at two and six months of age, LBW was associated with lower risk of subsequent mortality.

We set out to determine if LBW infants who are underweight at month two, which coincides with the age of first vaccination, could be assumed to be growing normally and at a lower risk of mortality than non-LBW underweight infants. We found that being underweight at two or six months of age is associated with a significantly increased risk of mortality irrespective of birth weight. Anthropometric changes observed since birth to two months were no better than a single measure at the point of vaccination in discriminating mortality risk.

LBW was associated with an increased risk of death during the first year of life. This risk is well-documented ¹⁴ . WHO guidelines recommend feeding LBW infants mother’s breastmilk for the first six months of life ¹⁵ , as this is associated with lower incidence of infections and necrotizing enterocolitis than those fed with infant formula ¹⁶ . There is also strong evidence for supplementation with Vitamin D, Iron and Calcium among very low-birth weight (VLBW) infants who are fed on mother’s breastmilk within the first six months of life ¹⁶ . In VLBW and LBW infants, vitamin D supplementation resulted in increases in height, weight, and MUAC in two randomised control trials ^{17, 18} . These specific interventions for LBW infants need to be implemented; however, the impact of growth monitoring programmes on growth and mortality of LBW infants is less clear ¹⁵ . A LBW infant tracking below the reference line may be inappropriately considered as “protected” from the risk of mortality because they were born small and apparently growing ‘normally’. Mothers of LBW infants where poor growth is recognised may be advised or initiate supplemental feeds before six months in an attempt to facilitate accelerated growth ¹⁹ , which may actually increase risk. There may also be maternal nutritional and health factors that influence feeding and care, which may usually be missed if the wellbeing of the mother is not assessed with that of her infant. Growth monitoring does present an opportunity if accompanied by informed assessment and appropriate action.

Emerging evidence suggests that proactive peer support to mothers of LBW infants improves compliance to exclusive breastfeeding in and out of the hospital environment ²⁰ . Our results indicate that at two months, infants identified to be underweight, irrespective of birth weight, are at increased risk of mortality and should receive targeted support. Underweight infants with a history of LBW should receive micronutrient supplementation as currently recommended, noting the existing gaps in guidance ¹⁶ .

We found that a single MUAC, WAZ or LAZ measure taken at two months of age discriminate mortality risk better than WLZ and that a single measure was better than change from birth. This is an important finding given that WLZ is the currently recommended criterion for intervention and among LBW infants, health worker may consider change in anthropometry more important than the single measure taken at growth monitoring. Our results concur with studies of community infants in The Gambia ²¹ and BukinaFaso ³ , and from hospital infant cohort in Kenya ²² and India ²³ where among infants u6m, WLZ is not reliably measured ^{24, 25} possibly partly explaining its poor prediction of subsequently mortality. Although using growth velocity may be better at identifying risk, in practice repeated measures may be more complex to implement ²⁶ . Current evidence suggests that using a MUAC cut-off of <11.0cm and WAZ<-3 when applied at two months (vaccination point) will effectively identify infants with a high risk of subsequent mortality ^{21, 22} . As a simple tool, MUAC may be applied at home by either community health workers or family members to help identify at risk infants early ²⁷ .

In many LMIC settings it is not feasible to distinguish LBW and NBW infants and so there is a need to identify early growth failure in infancy and determine intervention strategies appreciating that LBW infants will comprise a considerable proportion of these. To guide interventions, the Management of At risk Mothers and Infants (MAMI) care pathway approach leverages and connects existing services with active case identification and holistic management of the mother-infant dyad (Emergency Nutrition Network MAMI Tool 2018 available from: https://www.ennonline.net/c-mami).

A strength of this study was the large birth cohort with systematically collected monthly infant anthropometry up to one year of age and their vital status. However, the analysis at month two and six only used data from children with a measured anthropometry. Those excluded because of missing anthropometry could have differed with those included in this analysis. In the absence of ultrasound in pregnancy we were not able to distinguish risks from being preterm versus small for gestational age. A further limitation is that risks and care provision may now differ from those when the data were collected. The data used in this analysis was collected in 2004 and may not reflect improvements in infants care practices in the health system such as improvements in vaccination, community management of acute malnutrition.

In the first year of life, LBW infants are more likely to be underweight and continue to be at higher risk of mortality than NBW infants. To reduce risk of mortality among infants, research should focus on interventions to prevent LBW and on effective comprehensive interventions to reduce risks of mortality and promote neurodevelopment. Since LBW infants who are underweight have at least the mortality risk of non-LBW infants, all underweight infants need identification during screening or growth monitoring, to have individual nutritional, health and family assessment, and actions to address the risks associated with being underweight.