In the most recent NEJM two trials impacting newborn/paediatric care. One including 3,211 preterm infants, which shows that a very simple intervention could save, I estimate, tens of thousands of lives each year at almost no cost; the other with 50 infants, of one of the highest tech interventions possible, and which could make life immeasurably better for a tiny number of children, but which will probably have an extremely high price tag.
The prosaic first study was a randomized trial in “five tertiary-level hospitals in Ghana, India, Malawi, Nigeria, and Tanzania. All live-born infants in the participating hospitals whose birth weight was between 1.0 and 1.799 kg, regardless of gestational age, type of delivery, or singleton or twin status, were eligible for inclusion” WHO Immediate KMC Study Group. Immediate “Kangaroo Mother Care” and Survival of Infants with Low Birth Weight. N Engl J Med. 2021;384(21):2028-38. This trial randomized the low birth weight infants to either standard care, which involved separation of the mother and baby, with the baby placed in an incubator or with a radiant heater for at least 24 hours with no kangaroo care, then once they started to recover, defined as “CPAP not required, SpO2 90-94% on low concentration of additional oxygen (FiO2 <30% by nasal prongs), Tolerating partial enteral feeds (maybe on partial IV fluids)”, at which point the mother “will come to the SCNU to provide brief sessions of KMC a few times a day”.
Once a control group baby was more stable, defined as “when the following criteria are met for at least a continuous period of 24-hours:
(i) Breathing spontaneously without additional oxygen, and oxygen saturation on room air >90%
(ii) No need for CPAP
(iii) Respiratory rate 40 to <60 breathes per minute
(iv) No apnoea
(v) Heart rate 80 to <180 beats per minute
(vi) Axillary temperature 36.0 to 37.4°C
(vii) No need for intravenous fluids”
they were transferred to the Mother-NICU, units which were specially renovated spaces where Kangaroo Care was facilitated. These standards for the control babies followed current WHO guidelines.
The Mother–NICUs “included mothers’ beds and reclining chairs, were built or converted from existing NICUs. All equipment, staff, and care provision in the Mother–NICUs remained the same as in the control NICUs. At two sites, completely new Mother–NICUs were built in a nearby location and the existing NICUs were retained as the control NICUs. At the other three sites, modifications were made to convert half the existing NICUs to Mother–NICUs, and the other half served as the control NICUs. Infants receiving kangaroo mother care were secured firmly to the mother’s chest with a binder that ensured a patent airway.”
Babies randomized to the intervention were admitted as soon as possible after birth to the Mother-NICU, being randomized either before birth or as soon as possible afterwards, with a mean age of enrollment of about 30 minutes. The goal was to have the babies in KC for 20 hours a day, by the mother or a designated female relative (fathers are not allowed in the majority of the units!) Each had a KC support person who ensured they had access to food and toilets (as did the surrogate) and had routine obstetric postnatal care. The same approaches to neonatal care were employed as in the controls. The countries involved were, clearly very poor; the mothers enrolled had an average monthly family income of about 170 US dollars, and they were in countries where per capita annual health expenditures were as low as 35$ in Malawi, up to about 80$ in other involved countries.
The 28-day mortality in the controls was 15.7%, which was reduced to 12.0% with the immediate kangaroo care intervention. The study was, in fact, stopped early because of the mortality benefit in the intervention group, with no evidence of any harmful effect. The relative risk of death was 0.75 with KC, 95% CI 0.64, 0.89.
Previous studies of KC in low-income countries have also shown a benefit in reducing mortality, the Cochrane review notes a 40% reduction in mortality, but most studies were started after the baby was “stabilised” and therefore excluded a large number of deaths, those occurring soon after birth.
This intervention has the possibility of dramatically decreasing neonatal mortality in low and middle-income countries (NNT=27) at almost no cost; there may be some initial costs related to the logistics, which will not be huge, but may need specific budgets assigned in countries with such low health care expenditures. India and Nigeria, two of the countries involved in this trial, have the highest numbers of neonatal deaths in the world, with a combined 800,000 annual deaths of babies <28 days, much of which is related to low birth weight.
At the absolute opposite end of the health care spectrum, and in the same issue of NEJM, it now looks like gene therapy can “cure” children with ADA deficiency Severe Combined Immunodeficiency (ADA-SCID). Kohn DB, et al. Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency. N Engl J Med. 2021. This is a disease with an incidence somewhere around 1 per million live births, with the Adenosine Deaminase enzyme being hypo- or non-functional, leading to serious life-threatening, life-shortening, immune deficiency. Some of the states in the USA perform universal screening for this disorder, not because it makes any sense to screen, but because of family advocacy. That is a side issue, but it explains why the average age of patients in the 3 studies, reported together here, is much lower in the USA than in the UK. It is easy to understand why parents wanted neonatal screening, diagnosis is usually delayed until after the first couple of serious infections; however, there was previously no treatment, and the extreme rarity of the condition made it a questionable part of the routine neonatal screen. In the last few years, enzyme replacement therapy has been available and has improved the quality of life of the affected infants, which makes screening a bit more reasonable. This new study shows that administering gene therapy can provide long term improvement in ADA levels, prolonged high-quality survival and cessation of enzyme replacement. The study was partially supported by a commercial enterprise, Orchard Therapeutics, but with major funding by the NIH and the English Medical Research Council and other foundations.
Forty-eight of the 50 children studied had a sustained increase in their ADA levels, and had clinical improvements in their immune function. It is an amazing advance for the tiny number of infants with this condition, with a good probability that their lives may be almost normal after the intervention.
But I worry about what this might cost, and if crowd-funding initiatives will be necessary to get treatment for affected children; the example of Werdnig-Hoffman, Spinal Muscular Atrophy, does not give one much hope.
I also fear that the annual budget expenditure for one case of ADA-SCID in a high-income country may be more than the entire costs needed to implement immediate kangaroo care across the whole of Malawi.
Unfortunately the world makes no sense.