PROPHYLAXIS AND TREATMENT OF PRETERM BIRTH ASSOCIATED DEVELOPMENTAL DISORDERS

Abstract

A composition for the prophylaxis and/or treatment of a developmental disorder which is associated with preterm birth, and a method for the diagnosis and/or determination and/or prediction of the degree of severity of a developmental disorder which is associated with preterm birth.

Claims

1. A method for the prophylaxis and treatment of a developmental disorder in a preterm infant, said disorder is associated with preterm birth, comprising administering to said preterm infant a composition comprising docosahexaenoic acid (DHA) and choline.

2. The method of claim 1, wherein said composition is administered to such a preterm infant with a gestational age of ≦30 weeks.

3. The method of claim 1, wherein the developmental disorder which is associated with preterm birth, is of the lung, the brain or the eye.

4. The method of claim 1, wherein the developmental disorder which is associated with preterm birth is selected from the group consisting of: bronchopulmonary dysplasia (BPD), intelligence deficits, cerebral palsy, white matter disease, and retinopathy of prematurity.

5. The method of claim 1, wherein said composition additionally comprises arachidonic acid (ARA) or a precursor thereof.

6. The method of claim 5, wherein the precursor of ARA is all-cis-eicosa-8,11,14-trienic acid (DHGL).

7. The method of claim 5, wherein in said composition the ratio of DHA:choline:ARA/precursor is about 1:1:1 up to about 1:2:2.

8. The method of claim 1, wherein said composition is configured for an enteral, parenteral and/or oral administration.

9. The method of claim 1, wherein said composition does not comprise eicosapentaenoic acid (EPA) or ≦30 wt.-% of the DHA content.

10. The method of claim 1, wherein said composition is a pharmaceutical composition.

11. The method of claim 1, wherein said composition is a food supplemental composition.

12. A method for the determination of the degree of severity of a developmental disorder in preterm infants, which is associated with preterm birth, comprising the following steps: (1) providing a plasma sample of the preterm infant; (2) determining the ratio of arachidonic acid (ARA)-phosphatidyl choline (PC):docosahexaenoic acid (DHA)-phosphatidyl choline (PC) in the plasma sample; (3) inverse correlating the ratio of ARA PC:DHA-PC with the degree of severity of a developmental disorder which is associated with preterm birth.

13. The method of claim 12, wherein said plasma sample is a umbilical cord blood sample.

14. The method of claim 12, wherein the developmental disorder which is associated with preterm birth, is selected from the group consisting of: bronchopulmonary dysplasia (BPD), intelligence deficits, cerebral palsy, white matter disease, and retinopathy of prematurity.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0075] FIG. 1: Supply of preterm infants with enteral and parenteral choline (A) and fat (B). The data were calculated from individual patient files, and are indicated as medians (.diamond-solid., Δ). Thick bars represent the 25th and 75th percentiles and thin bars represent the minimum and maximum values of a total of 93 (one case of death at day 27) patients. The dashed line in (A) defines the calculated median “adequate intake” (Al) of the study group (27.4 mg/kg/d), whereas the grey box defines the calculated Al values for 1200 g (25.2 mg/kg/d) and 290 g (31.4 mg/kg/d) weight at birth weight.

[0076] FIG. 2: Postnatal changes in the plasma concentrations of choline (A), betaine (B) and dimethylglycine (C) in preterm infants. The data are indicated as medians and 25th/75th percentiles of n=13 (postnatal day d0-1), n=30 (d2-6), n=23 (d7-13), n=43 (d14-27) and n=53 (d28-84) postnatal plasma samples of preterm infants treated in hospital. The statistical analyses were performed by using the non-parametric Dunn test for group comparisons. Abbreviations: *, p<0.05, **, p<0.01, ***, p<0.001 compared to postnatal age d0-1.

[0077] FIG. 3: Differential postnatal changes of polyunsaturated phosphatidyl choline (PC; A) and phosphatidyl ethanolamine (PE; B) subgroups in preterm infants. Data are from 171 individual measurements in preterm infants which were treated in hospital, and indicate the postnatal kinetics of PC and PE subgroups with long chain polyunsaturated fatty acids, namely arachidonic acid (ARA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The data for ARA-PE and EPA-PE fitted linear regression models. ARA-PC, EPA-PC, DHA-PC and DHA-PE deviate from linearity and followed a model of two distinct first order kinetics. For the latter, individual regression lines are depicted before and after the respective breakpoints. Abbreviations: r, correlation coefficient; p, significance level.

[0078] FIG. 4: Changes in the fetal and maternal ARA-PC to DHA-PC ratio relative to the postmenstrual age of the fetus (A) and the degree of severity of the development of bronchopulmonary dysplasia (B). The ratios of ARA-PC to DHA-PC were determined from their respective concentrations in umbilical cord plasma (fetus) and maternal serum at the time of birth. Data in A indicate medians and 25th/75th percentiles in relation to the postmenstrual age, while data in B show individual measured points of patients with a high risk for BPD (below 28 weeks postmenstrual age at birth; N=34) and the linear regression line after testing for linearity. Abbreviations: PMA, postmenstrual age; r, correlation coefficient; p, significance level.

[0079] FIG. 5: Correlation between maternal and fetal PC subgroups throughout pregnancy (24-42 weeks postmenstrual age). The concentrations (A,B) and percentages (C,D) between 121 umbilical cord blood plasma (fetal) and the corresponding maternal blood sera (parturient). Abbreviations: Sat.-PC, saturated PC; C18:1-PC, oleic acid containing PC; C18:2-PC, linoleic acid containing PC; ARA-PC, arachidonic containing PC; EPA, eicosapentaenoic acid containing PC; DHA-PC, docosahexaenoic acid containing PC; PC, phosphatidyl choline; r, correlation coefficient; p, significance level.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0080] The invention relates to the treatment and prevention of developmental disorders of preterm infants, which are associated with preterm birth, in particular the bronchopulmonary dysplasia (BPD), by the application of a combined substitution von nutrients which are involved in the structure formation and functionality of parenchymatic organs in a fundamental manner. They include choline [2-hydroxy-N,N,N-trimethyl-ammonium], arachidonic acid (ARA) [all-cis-eicosa-5,8,11,14-tetraenoic acid; C20:4-ω-6] and docosahexaenoic acid (DHA) [all-cis-docosa-4,7,10,13,16,19-hexaenoic acid; C22:6-ω-3].

[0081] For these nutrients the inventors showed by means of an analysis of umbilical cord plasma and residues of clinically indicated blood samples the development of a postnatal deficiency. For choline a rapid postnatal decrease in concentration of approximately 50% of the fetal plasma concentration was demonstrated. For the choline-containing plasma phospholipid of phosphatidyl choline (PC) breakpoint analyses showed that the percentage of ARA and DHA-containing components in relation to the entire PC decreases by approximately 50% within 3 (ARA-PC) or 5.7 (DHA-PC) days. Therefore, this happened with preterm infants at an unphysiologically early point in time. In addition, ARA-PC further decreases during the treatment in hospital.

[0082] Analyses of umbilical cord plasma of very early preterm infants (24-28 weeks post conceptual age) showed that an initially low ratio of ARA-PC to DHA-DC is associated with the development and the degree of severity of the bronchopulmonary dysplasia (BPD). Therefore a low ratio of ARA-PC/DHA-PC at the birth predisposes for the development of the BPD or allows a prediction of the postnatal BPD development.

[0083] For this reason, the inventors have realized that by an early substitution of DHA and choline and, if applicable, additionally of ARA or their appropriate precursors in appropriate combination and dosage the formation of developmental disorders which are associated with preterm birth, in particular BPD, can be prevented. The supply of the composition according to the invention can be realized both per os in the context of the oral restorative diet and—e.g. in case of a clinically conditioned delay or interruption of this restorative diet—by the supply of an enteral or parenteral choline-, ARA- and DHA- containing emulsion/dispersion.

[0084] The phospholipide and choline analytics by means of tandem mass spectrometry allowed the inventors to examine the choline, DHA and ARA metabolism and its homeostasis in a targeted and differentiated manner.

[0085] With the invention it will be possible to prevent developmental disorders which are associated with preterm birth, in particular the frequent and chronic pathology of the bronchopulmonary dysplasia (BPD) of extremely small preterm infants (<30 weeks gestational age). The BPD is a serious pathology which in individual cases may result in death and in the majority of the cases it is associated with a long-lasting disorder of the lung function and the neurocognitive development.

[0086] It was realized by the inventors for the first time that there is a significant correlation between the addressed lipid metabolic parameters (ARA-PC/DHA-PC ratio) and the clinical pathology of the BPD in preterm infants, so that the descriptive lipid biochemistry results in a clinically applicable concept of the prophylaxis and treatment of developmental disorders which are associated with preterm birth, in particular the BPD.

[0087] Furthermore it was also realized for the first time that a nutrient combination based on the high demand of the preterm infant and the metabolism of long chain polyunsaturated fatty acids which are essential to fetus (ARA, DHA) can be used for the prevention of developmental disorders which are associated with preterm birth, in particular the bronchopulmonary dysplasia (BPD). The metabolism of ARA and DHA is coupled to the one of choline which results in a reasonable triple combination.

[0088] Furthermore, it was realized for the first time that a prediction of developmental disorders, in particular of BPD, is enabled by a measurement of the ratio of ARA-PC/DHA-PC in the umbilical cord blood or in the first days of life, which allows a targeted treatment or prevention of treatment side effects in children with low risk.

[0089] The advantages of the invention lie in the fact that the problem of inadequate development of preterm infants, in particular of their lung, is addressed by a targeted and adapted and combined administration of the precursors which are essential for the metabolism and the structure formation of the premature lung, however which are not sufficiently supplied to preterm infants, as it was now discovered.

[0090] An effective nutritive instrument of the BPD prophylaxis constitutes a major progress in the treatment of extremely immature preterm infants, which has not been solved in a satisfactory manner by any previous pharmacological approaches. The combined administration of choline, DHA and, if applicable, ARA (and/or its precursors DHGL), is therefore a significant instrument in the prophylaxis of developmental disorders which are associated with preterm birth, in particular the BPD, and the replacement of/complement to anti-inflammatory therapeutics (catabolically and especially in preterm infants cerebro- and cerebello toxically effective glucocorticoids) and other pharmaceuticals.

[0091] The inventors have carried out in the past investigations of the choline and phosphatidyl choline (PC) homeostasis in mothers (perinatal blood serum), fetuses (umbilical cord blood plasma) and in preterm infants treated in hospital (24-42 weeks postmenstrual gestation age (PMA)). The investigations showed that the choline supply of preterm infants is not sufficient and, in particular, discontinuous, in contrast to the situation in utero (FIG. 1; from Bernhard et al. (2013; I.c.)). The investigations of the inventors also show that the concentration of choline in plasma post partum decreases within 48 hours to 50% of the physiological value which means—for a high Michaelis constant of non-synaptic choline carrier—a halving of the tissue intake (FIG. 2; from Bernhard et al. (2014), Eur. J. Nutr. of Aug. 23, 2014, I.c.). In the same way the percentage of the ARA- and DHA-containing phospholipids, in particular of the choline-containing phosphatidyl choline (PC) is reduced by approximately 50% within 3 (ARA-PC) or 5.7 (DHA-PC) days post partum. These values do not normalize postnatal (ARA-PC) or do so only substantially delayed (DHA-PC) to the values which correspond to the postconceptional age (FIG. 3; Bernhard et al. 2014), Eur. J. Nutr. 53(7):1533-47).

[0092] New pair analyses of phospholipids of umbilical cord plasma and maternal serum were carried out and in particular (1) the dependency between the maternal and fetal phospholipid state was determined, and (2) its relation to the bronchopulmonary dysplasia (BPD), the most frequent long lasting vegetative impairment of former preterm infants, was analyzed.

[0093] It has been found that the ratio of ARA-PC to DHA-PC in particular in very small preterm infants is high (FIG. 4A). It further has been surprisingly found that a low ARA-PC/DHA-PC ratio correlates with the incidence and the degree of severity of the BPD (r=−0.7397; p=0.0003) (FIG. 4B).

[0094] The comparison of maternal and fetal PC further showed that the initial neonatal concentrations of ARA-PC and DHA-PC correlate with maternal values, so that the target group of very immature preterm infants is born with different levels of ARA and DHA “load” (FIG. 5).

[0095] In addition to these results it has been demonstrated that the measurement of the ARA-PC/DHA-PC ratio provides a new predicative parameter.