Brener Dik PH, et al. Early hypophosphatemia in preterm infants receiving aggressive parenteral nutrition. J Perinatol. 2015;35(9):712-5. This group of neonatologists in Buenos Aires routinely give 3 g/kg/d of lipid, 3 to 3.5 g/kg/d of amino acids, 40 mg/kg/d of calcium gluconate and 20 mg/kg/d of glycerophosphate starting on day 1 to their babies under 1250 grams. By day 6 the babies were often hypercalcemic and hypophosphatemic, especially the IUGR babies. Babies who were more unwell in the first days of life were also more likely to have a low phosphate. 40 mg of calcium gluconate is slightly less than 0.1 mmol of calcium, 20 mg/kg/d of sodium glycerophosphate is about 0.1 mmol/kg/d of phosphorus.

Boubred F, et al. Extremely preterm infants who are small for gestational age have a high risk of early hypophosphatemia and hypokalemia. Acta Paediatr. 2015. In Sweden they give less nutrition on day 1; 2 g/kg/d of protein, 1 g/kg/d of lipid and 6 g of glucose, and then ramp it up over 4 days. On day 1 they give very little phosphorus, thereafter the babies were receiving about 0.6 mmol/kg/d of calcium, and between 0.5 and 0.6 mmol/kg/d of phosphorus. The IUGR babies were much more likely to develop low serum phosphates, and again the peak seems to be about day 4.

Moe K, et al. Administering different levels of parenteral phosphate and amino acids did not influence growth in extremely preterm infants. Acta Paediatr. 2015;104(9):894-9. In this observational study from Copenhagen they report 3 cohorts of preterm babies, in the middle cohort there was an error in their TPN software, so they gave much less phosphorus to the babies, especially during the first 3 days of life, when there was about 0.07 mmol/100 ml of TPN. The babies who got this regime had much more hypophosphatemia, especially if they were IUGR; the authors didn’t find a difference in growth during the first month of life.

Three other recent articles address these issues also :

Bonsante F, et al. Initial amino acid intake influences phosphorus and calcium homeostasis in preterm infants–it is time to change the composition of the early parenteral nutrition. PLoS One. 2013;8(8):e72880. This article (free access) reports a cohort study with varying protein intakes in preterm infants, the babies were all treated in the University hospital in Dijon, but, interestingly none of the authors’ current affiliations are with that hospital, they are from Réunion, Italy and Belgium. They show that the babies who received more amino acids had more hypophosphatemia, even though they also received more phosphorus. The high AA group received 21 mg/kg/d of phosphorus which is about 0.67 mmol/kg/d.

Christmann V, et al. Early postnatal calcium and phosphorus metabolism in preterm infants. Journal of pediatric gastroenterology and nutrition. 2014;58(4):398-403. In this study from Nijmegen babies received much more calcium and phosphorus, quickly getting up to 3 mmol/kg/d of calcium and 1.92 mmol/kg/d of phosphorus, by day 3. By day 4 to 5 many of their babies were hypophosphatemic, and hypercalcemic, at which time they had almost no phosphorus in the urine. So although they were getting lots of phosphorus, it looks like the ratio was not correct.

Pereira-da-Silva L, et al. Early High Calcium and Phosphorus Intake by Parenteral Nutrition Prevents Short-term Bone Strength Decline in Preterm Infants. Journal of Pediatric Gastroenterology & Nutrition. 2011;52(2):203-9. This is the only reference in today’s post that is actually an RCT, from Lisbon this time. About 40 preterm babies per group were randomized to different intakes of Calcium and Phosphorus in their TPN. They either got 45 mg/kg/d of calcium (1.1 mmol) with 36 mg/kg/d of phosphorus (1.16 mmol)  or 75 mg/kg/d of calcium (1.9 mmol) and 44 mg/kg/d of phosphorus (1.42 mmol), which usually started on day 1. The enteral feeds were not changed, so by the end of the first week there was little difference between the groups, and the macronutrient supply was also similar. From week 3 to week 6 there was a progressive reduction in bone strength in the low mineral group, and no reduction in the high group. The authors do not report the incidence of hypophosphatemia.

One thing this review has taught me is that the reporting of mineral intakes and metabolism in preterm infants is often really unclear, even when the study is concentrating on minerals. Could we all please report intakes and balances in mmol?

The other things that are clear, (and I must claim clairvoyance because our TPN standards here have said this for years) is that the requirements for calcium and phosphorus in the first few days of life are not the same as later on in the life of the preterm. The ratio between calcium and phosphorus should be higher for the first few (3-4?) days. Phosphorus is important for cellular metabolism as well as for bone growth. In those first few days we should aim to give enough phosphorus for those requirements, and to avoid hypophosphatemia. At the same time avoiding hypercalcemia and hypocalcemia are important. We might need to give as much as a 1:1 ratio of calcium to phosphorus just after birth, and then progressively switch to a ratio of about 1.6:1 (in mmol).

In fact the paper by Bonsante (a great name for a physician!) suggests something similar, they propose that the appropriate P intake (in mg/kg/d) might be calculated by dividing the Ca intake (also in mg/kg/d) by 2.15 and adding the amino acid intake (in g/kg/d) -1.3 multiplied by 9.8. If a baby is getting 2.5 g/kg/d of amino acids, and 40 mg (1 mmol)/kg/d of calcium this would work out to about 31 mg of phosphorus, which is almost exactly 1 mmol. If they are getting more protein, they would receive a bit more phosphorus, which is consistent with the data from those studies above.

Once the baby starts to grow consistently, then more phosphorus is laid down in bone, and we should probably aim for a ratio of nearer to 1.66 :1 (in mols), which is the ratio of calcium to phosphorus in new bone.

The recommendations of ESPGHAN published in 2005 (available free on-line) only discuss requirements during the growing phase of the preterm, and not during the first few days. They refer to a calcium phosphorus ratio of between 1.3:1 and 1.7:1 (in mols). The total intake they suggest is to vary according to weight gain, and to give 4 mmol of calcium for every 20 g of weight gain. Which I think is difficult to put into practice, as this suggests that you can only decide on how much calcium and phosphorus to give after the babies have already received the TPN and you see how well they grow!

The increased risk of hypophosphatemia in IUGR babies is similar to a “refeeding syndrome” although Bonsante’s group suggest not using that term, they suggest “placental interrupted feeding syndrome” instead, in order to note that you don’t have to be severely malnourished to develop these findings, they occur in AGA preterm also. Do IUGR babies, in the first days of life, need more phosphate? Do they need a higher ratio of phosphorus to calcium? Or both? I think some more observational studies with a higher P administration and an appropriate ratio might help us to know.