Fetal and Neonatal Oxygen Delivery

Fetal hematocrit and hemoglobin concentrations gradually increase as gestation increases. Fetal erythropoiesis is stimulated by fetal erythropoietin (Epo), produced in response to the fetal hypoxic environment ( Fig. 44.1 ), where P o ₂ values range from 20 to 35 torr ( Fig. 44.2 ). Oxygen extraction from the placental circulation is augmented by the high percentage of fetal hemoglobin, which has a greater oxygen affinity than adult hemoglobin ( Fig. 44.2 ). P o ₂ values increase once an infant is born, resulting in a rapid decline in Epo production and cessation of erythropoiesis.

Erythropoietin (Epo) and Downstream Signaling.

(A) Epo is a globular molecule composed of four helices, where the helix B (encircled in red ) has stayed highly conserved during evolution. Epo binds a homodimeric cognate receptor and bridges two sites (dashed boxes) , and the consequential conformational change results in phosphorylation of JAK2 and triggers multiple downstream molecular cascades (not shown). (Modified after permission to reproduce from Brines M. Extrahematopoietic actions of erythropoietin. In: Textbook of Nephro-Endocrinology , ch. 23, 411–428.) (B) Hypoxemia and anemia induce Epo expression, a process that involves the hepatic nuclear factor 4 (HNF-4) and the hypoxic inducible factor-1 (HIF-1; not shown). HNF-4 binds the Epo promoter and enhancer regions and is highly expressed in the kidneys and liver. HIF-1 is a basic helix-loop-helix transcription factor that binds the cis -acting hypoxia-response elements to induce Epo transcription. Although there is some evidence to suggest that HIF-1 is expressed during fetal development, the regional expression of these transcriptional activators needs further investigation.

Oxyhemoglobin (Hb o ₂ ) Equilibrium Curves.

(A) Blood from term infants at birth. (B) Blood from adults. a , arterial; v , venous.

Acute and Chronic Anemia

Anemia occurs when the volume of circulating red cells fails to meet the metabolic needs of tissues. Preterm infants born <1500 g (very low birth weight [VLBW]) are frequently transfused due to common clinical characteristics and features of prematurity that, compounded, result in a significant fall in hemoglobin and hematocrit in the first weeks of life. These characteristics include (1) lower hemoglobin concentrations at lower gestational ages ( Fig. 44.3 ); (2) ongoing loss of red cells due to phlebotomy, sometimes equaling an entire blood volume (80–85 mL/kg) in the first weeks of life; (3) a shortened red cell life span of 60 to 70 days; and (4) lack adequate endogenous Epo production after birth to maintain the red cell mass. All of these characteristics lead to a fall in hemoglobin and hematocrit that is greater than that seem normally in term infants during their physiologic nadir ( Fig. 44.4 ), resulting in frequent transfusions.

Changes in Hemoglobin Concentration (g/dL) From 22 to 42 Weeks’ Gestation.

The dotted lines represent the 5th and 95th percentiles; the solid line represents the mean.

Mean Hemoglobin and Reticulocyte Values in Term and Preterm Infants.

Infants born preterm become anemic earlier in the postnatal period with hemoglobin concentrations returning to normal later. Black , Lower range of normal; gray , upper range.

Indications for neonatal transfusions differ based on the rate of fall in hemoglobin. In an infant with acute blood loss, the need for a transfusion is generally dependent on persistent clinical signs of inadequate oxygen delivery following the restoration of intravascular volume. Infants with chronic anemia may also exhibit clinical signs of inadequate oxygen delivery such as increased resting heart rate, acidosis, poor growth, and apnea, and a need for increased respiratory support, that are often ameliorated by a transfusion.

Red cell transfusions are currently the accepted treatment for acute anemia, especially anemia due to hemorrhage, because they rapidly increase available oxygen. The oxygen content is based on the following equation:

In this equation, 1.34 equals the mL of oxygen binding to each gram of hemoglobin, and 0.003 equals the mL of oxygen dissolved in blood per mm Hg. Oxygen availability and delivery to tissues is proportional to oxygen content and cardiac output. When cardiac output is adequate and optimized, red cell transfusions rapidly increase oxygen availability to tissues. There are, however, a growing list of risks associated with transfusions, including transmission of infection, graft-versus-host disease, transfusion-related acute lung injury, transfusion associated circulatory overload, and toxic contamination of blood products with heavy metals. In the preterm infant population, red cell transfusions may be associated with an increased risk of necrotizing enterocolitis (NEC), extension of intraventricular hemorrhage (IVH), increased mortality, or impaired developmental outcome. ^, A causal relationship with any of these adverse events is still being determined. Neonatal transfusions can result in increases in proinflammatory cytokines such as ICAM-1, IL-1β, IL-8, IL-10, IFN-γ, IL-17, and MCP-1, potentially increasing or worsening morbidities associated with prematurity. These potential complications underscore the need to carefully evaluate the need for a rapid increase in oxygen availability to tissues prior to ordering a nonemergent transfusion in a preterm infant. Similar to the growing emphasis on antibiotic stewardship, where antibiotics are being reassessed and more stringently prescribed, “transfusion stewardship” will hopefully provide greater focus for providers to practice evidence-based ordering of blood products for neonates.

It can be a challenge determining which neonate with a low hematocrit will benefit from a red cell transfusion. Many preterm infants can adapt to a slowly decreasing hematocrit and can be treated conservatively with supplemental iron and red cell growth factors such as Epo or darbepoetin (Darbe) to avoid the associated risks of transfusion. ^, Target hemoglobin and hematocrit have been used as clinical indicators for red blood cell (RBC) transfusion; however, it remains uncertain what target hematocrit or hemoglobin will optimally balance the risks and benefits of this intervention. This chapter focuses on exploring the development of evidence-based transfusion guidelines in the newborn intensive care unit (NICU).

Transfusion Studies in Critical Care

Over the past 4 decades, approaches to RBC transfusions in neonates have changed significantly. In the 1980s, phlebotomy losses in NICU patients were carefully recorded in order to replace blood lost when losses reached 10 mL/kg. Transfusions were generally administered when a preterm infant’s hematocrit dropped below 40%, and “top-off” transfusions (5–10 mL/kg volumes) were common in the later weeks of NICU hospitalization. Signs typical of preterm infants, such as apnea, poor feeding, tachycardia, and poor weight gain, were ascribed to anemia, and infants would be transfused frequently over a wide range of hematocrits without clear evidence of benefit.

Development of transfusion guidelines in critical care became a priority for Canadian institutions after thousands of transfusion recipients were exposed to hepatitis C and HIV from contaminated blood. A number of Canadian multicenter trials in populations receiving frequent transfusions ensued. The Transfusion Requirements in Critical Care (TRICC) trial randomized stable critical care patients to a restrictive hemoglobin transfusion threshold of 7 g/dL or a liberal transfusion threshold of 9 g/dL. Those in the restrictive group received fewer transfusions with better outcomes and lower in-hospital mortality (22.2% versus 28.1%). In a similarly designed trial performed in stable pediatric critical care patients, a hemoglobin threshold of 7 g/dL for red-cell transfusion decreased transfusion requirements without increasing adverse outcomes.

Neonatal Transfusion Studies

Neonatal transfusion practices did not begin to change until the mid-1990s, following publication of the first multicenter trial of Epo administration to VLBW infants. The study implemented a transfusion protocol that was subsequently implemented in many NICUs throughout the country. As a result, the average number of transfusions administered to VLBW infants decreased significantly. In order to identify strategies that would decrease the need for red blood cell transfusions and to limit donor exposure in VLBW infants, the Canadian Paediatric Society adopted guidelines that were even more restrictive than those used in the US Epo study ( Table 44.1 ). In fact, these guidelines, published in 2002, remain the most restrictive guidelines for neonates published to date.

Since the early 2000s, a number of studies have been performed evaluating hematocrit thresholds for transfusion in preterm infants. Bifano and colleagues were the first to compare higher and lower transfusion thresholds. They randomized 50 extremely low birth weight (ELBW) infants to maintain hematocrits above 32% or below 30%. Despite a difference in hemoglobin between groups of over 4 g/dL, they found no differences in hospital outcomes, growth, or neurodevelopment at 1 year. ^{, ,}

Bell and colleagues randomized 100 preterm infants with a birth weight of 500 to 1300 g to a liberal (higher hematocrit) or restrictive (lower hematocrit) transfusion threshold strategy, based on level of respiratory support, age, and clinical status. Clinical outcomes were compared. Infants in the liberal-transfusion group received more RBC transfusions (5.2±4.5) compared with the restrictive-transfusion group (3.3±2.9). There were no differences in pretransfusion cardiac output, hospital days, or survival to discharge. Investigators found an increase in grade 3 or 4 IVH or periventricular leukomalacia in the restrictive group (6/28 versus 0/24 in the liberal group). They concluded that more frequent major adverse neurologic imaging findings in the restrictive group suggested restrictive transfusions might be harmful.

Long-term follow-up of infants enrolled in the Iowa trial was performed on a subset of children available for evaluation at 12 years. Both cognitive function (based on developmental assessment) and magnetic resonance imaging outcomes were better in the restrictive group. ^,

Canadian investigators designed a large multicenter trial to evaluate transfusion thresholds on hospital outcomes. Investigators for the Premature Infants in Need of Transfusion (PINT) Study randomized 451 ELBW infants to a high or low threshold transfusion strategy within 48 hours of birth. Infants in the low threshold group received fewer transfusions and were transfused at a later age. There were no differences in morbidities or mortality between the low and high hemoglobin threshold groups, resulting in no difference in the composite outcome of death or serious morbidity at the time of discharge (bronchopulmonary dysplasia, severe retinopathy of prematurity, or, importantly, brain injury identified on ultrasound). At 18 to 21 months’ corrected age there were no differences between the low and high target hematocrit groups in the composite outcome of death or neurodevelopmental impairment, defined as cerebral palsy, significant visual or hearing impairment, or a Bayley Scales of Infant Development II (BSID II) Mental Development Index (MDI) score <70. In post hoc analyses using an MDI score <85 instead of <70, the primary outcome of death or neurodevelopmental impairment (NDI) was more likely in the low hematocrit group (45%) compared with the high hematocrit group (34%), leading investigators to hypothesize that maintaining a higher hematocrit would decrease the incidence of NDI in preterm infants.

A 2012 meta-analysis included both the Iowa and PINT studies and reported no difference in morbidities or mortality rates between high and low threshold transfusion groups. Similar to adult and pediatric critical care populations, a restrictive (low) hematocrit threshold compared with a liberal (high) threshold (hematocrit 35%–40%) resulted in fewer transfusions with no increase in mortality or serious morbidity. ^, Because of concerns that long-term developmental impairment might still be associated with restrictive transfusion strategies, two similarly designed, large randomized trials were performed—one in Europe and the other in the NICHD Neonatal Research Network, published in 2020—that overwhelmingly confirmed the results of the previous meta-analyses. These studies are reviewed below.

Hematocrit Triggers for Transfusion

Hematocrit triggers were determined for each trial ( Table 44.2 ). For the TOP trial, a survey of neonatologists was performed to determine an acceptable range of hematocrits that could be used to trigger transfusions. Hematocrit triggers were chosen to achieve a statistical difference in hemoglobin between the low and high groups of 2 to 2.5 g/dL (hematocrit 5%–6%). In the ETTNO study, transfusion triggers were guided by current clinical practice in Germany. The high and low thresholds chosen also aimed to produce a clinically relevant difference in mean hemoglobin concentrations between treatment groups of about 2 g/dL, in order to improve recognition of any effect of hemoglobin thresholds on neurocognitive outcome compared with the PINT trial, where differences between high and low thresholds were narrower.

Table 44.2

Transfusion Triggers for the TOP ^a and ETTNO ^b Studies

	TOP High Respiratory Support	TOP High No Respiratory Support	TOP Low Respiratory Support	TOP Low No Respiratory Support	ETTNO High Critical	ETTNO High Noncritical	ETTNO Low Critical	ETTNO Low Noncritical
0–7 days	38	35	32	29	<41	<35	<34	<28
8–14 days (TOP) 8–21 days (ETTNO)	37	32	29	25	<37	<31	<30	<24
≥15 days (TOP) >21 days (ETTNO)	32	29	25	21	<34	<28	<27	<21

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