Information
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Patent Application
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20020137796
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Publication Number
20020137796
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Date Filed
February 28, 200024 years ago
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Date Published
September 26, 200221 years ago
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CPC
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US Classifications
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International Classifications
Abstract
A method for enhancing the growth of preterm infants involving the administration of certain long chain polyunsaturated fatty acids. It is preferred that the infants are administered an infant formula containing a combination of docohexaenoic acid and arachidonic acid.
Description
FIELD OF INVENTION
[0001] The present invention concerns enhancing the growth of preterm infants involving administration of infant formula containing a combination of docosahexaenoic and arachidonic acid.
BACKGROUND OF THE INVENTION
[0002] The long chain polyunsaturated fatty acids (LC PUFA) have been shown to be important in infant development. Particularly, arachidonic acid (ARA) and docosahexaenoic acid (DHA) are LC PUFA that are of special interest in infant nutrition because they are found in high concentrations in the brain (Sastry P S, Lipids of nervous tissue: composition and metabolism. Progress Lipid Res 1985;24:69-176) and the retina (Fliesler S J and Anderson R E. Chemistry and metabolism of lipids in the vertebrate retina Progress Lipid Res 1983;22:79-131). ARA (20:4n-6) and DHA (22:6n-3) are derived from the parent essential fatty acids linoleic acid (18:2n-6) and α-linolenic acid (18:3n-3) through alternate desaturation and elongation and accumulate rapidly in fetal neural tissue during the last months of gestation and the first months of postnatal life (Makrides M, Neuman M A, Byard R W, Simmer K, Gibson R A. Fatty composition of the brain, retina and erythrocytes in breast- and formula-fed infants. Am J Clin Nutr 1994;60:189-94).
[0003] Unlike term infants, preterm infants do not fully benefit from the maternal and placental LC PUFA supply during the last trimester of pregnancy. Even though preterm infants are capable of synthesizing both DHA and ARA from their 18 carbon precursors (Camielli V P, Wattimena D J L, Luijendijk I H T, Boerlage A, Degenhart H J, Sauer P J J. The very low birth weight premature infant is capable of synthesizing arachidonic and docosahexacnoic acids from linoleic and linolenic acids. Pediat Res 1996;40:169-174), it remains unclear whether the rate of synthesis is adequate to meet the optimal needs for central nervous system accretion in the absence of a dietary supply of these fatty acids. Preterm infants are dependent on their own dietary supply of linoleic and α-linolenic acids through either human milk, which also contains small but significant amounts of ARA and DHA or through commercially available artificial formulas, none of which in the United States contain ARA and DHA.
[0004] It has been demonstrated in recent studies (Hoffman D R and Uauy R. Essentiality of dietary ω-3 fatty acids for premature infants: Plasma and red blood cell fatty acid composition. Lipids 1992;27:886-95) that the fatty acid composition of red blood cell membrane lipids in infants receiving formulas supplemented with DHA (0.35% of total fatty acids) was similar to human milk-fed infants. In the same study, Birch (Birch D G, Birch E E, Hoffman D R, Uauy R D. Retinal development in very-low-birth-weight infants fed diets differing in Omega-3 fatty acids. Investigation Ophthalmology Visual Science 1992;33:2365-76) found that retinal function improved with the provision of a dietary supply of DHA in very low birth weight infants.
[0005] The first year growth of preterm infants fed standard formula compared to marine oil LC PUFA supplemented formula was studied by Carlson et al. (Carlson S E, Cooke, R J, Werkman S H, Tolley E A. First year growth of preterm infants fed standard compared to marine oil n-3 supplemented formula Lipids 1992:27:901-907). The experimental formulas provided 0.2% of total fatty acids as DHA and also provided 0.3% as EPA (20:5n-3). This EPA concentration is higher than found in human milk while the DHA level is similar to human milk. Beginning at 40 weeks from conception, marine oil supplemented infants compared to controls had significantly lower weight, length, and head circumference. From this study, Carlson (Carlson S E, Werkman S H, Peeles J M, Cooke R J, Tolley E A. Arachidonic acid status correlates with first year growth in preterm infants. Proc Natl Acad Sci USA 1993;90:1073-77) hypothesized that dietary ARA could improve first year growth of preterm infants, in the context of restoring growth to the level of control formula containing no LC PUFA.
[0006] In another study (Montalto, F B, et al., Pediatric Research, Vol 39, page 316A, abstract no. 1878) it was shown that male infants fed marine oil supplemented formula (containing DHA but essentially no ARA) had, by 4 to 6 months, lower head circumference, length, weight and fat free mass than standard formula fed infants. A third study also showed decreased weight at 9 and 12 months corrected age in preterm infants fed marine oil supplemented formula (with LC PUFA) to 2 months corrected age compared with control formula containing no LC PUFA (Carlson S E, et al., Am. J. Clin. Nutr., 63 pp 687-97, 1996).
[0007] The prior art has demonstrated that infants with altered tissue LC PUFA levels, resulting from a lack of LC PUFA in their diets, may be at risk for neurological problems, may also have reduced scores on cognitive tests, and may have lower retinal development than human milk-fed infants. Worldwide regulatory organizations such as the WHO/FAO Expert Committee on Fats and Oils in Human Nutrition have recommended that LC PUFA be included in preterm infant formula. These recommendations have been made despite the negative effects observed of DHA supplements on growth. There has been no demonstration in the literature that ARA and DHA, particularly when added to infant formula, enhances the growth of infants above that demonstrated by control formulas not containing ARA and DHA.
SUMMARY OF THE INVENTION
[0008] It has unexpectedly been discovered that preterm infants receiving infant formula supplemented with both DHA and ARA demonstrate enhanced growth. The present invention is directed to enhancing the growth of preterm infants comprising administering to said infants a growth enhancing amount of DHA and ARA.
DETAILED DESCRIPTION OF THE INVENTION
[0009] As reported in a review of preterm infant growth by Carlson, S E, (The Jrnl of Pediatrics, Vol 125, pp 533-8, 1994) “After adjusting for postconceptional age, preterm infants show a decline (rather than a catch-up) in the normalized weight from approximately 2 to 4 months past expected term.”
[0010] Several prior art studies have documented the value of administering DHA to infants. However, when DHA, either as the primary LC PUFA or combined with EPA, is administered to preterm infants, said infants suffer from decreased growth. It has been suggested that ARA may be beneficial to growth; however, heretofore the growth effects of administering both DHA and ARA to preterm infants have been unknown. It has been surprisingly discovered that administering the combination of ARA and DHA results in enhanced growth of infants relative to infants fed DHA alone. It has also been discovered that preterm infants administered an infant formula containing ARA and DHA exhibit enhanced growth relative to preterm infants fed control formula without DHA and ARA, such as those formulas currently used in modem nurseries. It has further been discovered that practice of the method of the invention results in growth of preterm infants catching up in an unexpected short time to a reference group of normal term breast fed infants.
[0011] The time to achieve growth similar or equivalent to normal term breast fed infants by practice of the method of the invention is less than 9 months corrected age; preferably less than 6 months corrected age, more preferably less than 4 months corrected age, even more preferably less than 2 months corrected age, and most preferably no greater than term corrected age.
[0012] The method of the invention requires a combination of DHA and ARA. The weight ratio weight of ARA:DHA can be about 1:2 to about 5:1, preferably about 1:1 to about 3:1, and more preferably about 2:1.
[0013] In the method of the invention the combination of DRA and ARA is preferably administered as part of an infant formula. The infant formula for use in the present invention is preferably nutritionally complete and typically contains suitable types and amounts of lipid, carbohydrate, protein, vitamins and minerals. The amount of lipid or fat typically can vary from about 3 to about 7 g/100 kcal. The amount of protein typically can vary from about 1 to about 5 g/100 kcal. The amount of carbohydrate typically can vary from about 8 to about 12 g/100 kcal. Protein sources can be any used in the art, e.g., nonfat milk, whey protein, casein, soy protein, hydrolyzed protein, amino acids, and the like. Carbohydrate sources can be any used in the art, e.g., lactose, glucose, corn syrup solids, maltodextrins, sucrose, starch, rice syrup solids, and the like. Lipid sources can be any used in the art, e.g., vegetable oils such as palm oil, soybean oil, palmolein, coconut oil, medium chain triglyceride oil, high oleic sunflower oil, high oleic safflower oil, and the like. Conveniently, commercially available infant formula can be used. For example, Enfamil®, Enfamil® Premature Formula, Enfamil® with Iron, Lactofree®, Nutramigen®, Pregestmil®, ProSobee® (available from Mead Johnson & Company, Evansville, Ind., U.S.A.), Similac®, Isomil®, Alimentun®, Neocare®, and Similac® Special Care (available from Ross Laboratories, Columbus, Ohio, U.S.A.), may be supplemented with suitable levels of ARA and DHA at the proper ratios and used in practice of the method of the invention.
[0014] The form of administration of the DHA and ARA in the method of the invention is not critical, as long as a growth enhancing amount is administered. Most conveniently, the DHA and ARA are supplemented into infant formula which is then fed to the infants. Alternatively, the DHA and ARA can be administered as a supplement not integral to the formula feeding, for example, as oil drops, sachets, in combination with other nutrient supplements such as vitamins, and the like.
[0015] The growth enhancing amount of DHA is typically about 2.5 mg/kg of body weight/day to about 60 mg/kg of body weight/day, preferably about 6 mg/kg of body weight/day to about 40 mg/kg of body weight/day, more preferably about 12 mg/kg body weight/day to about 30 mg/kg body weight/day, and even more preferably about 18 mg/kg of body weight/day to about 24 mg/kg of body weight/day.
[0016] The growth enhancing amount of ARA is typically about 5 mg/kg of body weight/day to about 120 mg/kg of body weight/day, preferably about 12 mg/kg of body weight/day to about 80 mg/kg of body weight/day, more preferably about 24 mg/kg body weight/day to about 60 mg/kg body weight/day, and even more preferably about 36 mg/kg of body weight/day to about 48 mg/kg body weight/day.
[0017] The amount of DHA in infant formulas for use in the present invention typically varies from about 2 mg/100 kilocalories (kcal) to about 50 mg/100 kcal, preferably about 5 mg/100 kcal to about 33 mg/100 kcal, more preferably about 10 mg/100 kcal to about 25 mg/100 kcal, and even more preferably about 15 mg/100 kcal to about 20 mg/100 kcal.
[0018] The amount of ARA in infant formula for use in the present invention typically varies from about 4 mg/100 kcal to about 100 mg/100 kcal, preferably about 10 mg/100 kcal to about 67 mg/100 kcal, more preferably about 20 mg/100 kcal to about 50 mg/100 kcal, and even more preferably about 30 mg/100 kcal to about 40 mg/100 kcal.
[0019] The infant formula supplemented with oils containing DHA and ARA for use in the present invention can be made using standard techniques known in the art. For example, replacing an equivalent amount of an oil normally present, e.g., high oleic sunflower oil.
[0020] The source of the ARA and DHA can be any source known in the art such as fish oil, single cell oil, egg, yolk lipid, brain lipid, and the like. The DHA and ARA can be in natural form, provided that the remainder of the LC PUFA source does not result in any substantial deleterious effect on the infant. Alternatively, the DHA and ARA can be used in refined form. It is preferred that the LC PUFA used in the invention contain little or no EPA. For example, it is preferred that the infant formulas used herein contain less than about 20 mg/100 kcal EPA; preferably less than about 10 mg/kcal EPA; more preferably less than about 5 mg/100 kcal EPA; and most preferably substantially no EPA.
[0021] Preferred sources of DHA and ARA are single cell oils as taught in U.S. Pat. Nos. 5,374,657, 5,550,156, and 5,397,591, the disclosures of which are incorporated herein by reference in their entirety.
[0022] The following examples are to illustrate the invention but should not be interpreted as a limitation thereon.
CLINICAL STUDY DESIGN
[0023] 1. INTRODUCTION
[0024] This study is a double-blind, randomized, controlled parallel design, prospective trial of premature infant formulas containing microalgae and fungi-derived oils which contain a part of their constituents arachidonic acid and docosohexaenoic acid. Formula feeding subjects will be randomized into one of 3 feeding groups:
[0025] premature formula plus DHA (about 0.13% of energy) and ARA (about 0.26% of energy)
[0026] premature formula plus DHA (about 0.13% of energy)
[0027] premature formula WITHOUT DHA and ARA
[0028] The products have the same nutrient composition (see Appendix A) and differ only in the level of DHA and ARA. The products will be blinded. The present order of formula has no relationship to randomization.
[0029] Normal, term, breast fed infants will be enrolled to provide a normal visual acuity reference.
[0030] Fifty evaluable subjects will be completed in each group. Premature infants will remain on study formulas after reaching 90 kcal/kg/d for a minimum of 28 days or until hospital discharge whichever is longer. After 28 days or discharge, whichever is longer, all premature infants will receive Enfamil or Enfalac with Iron. If medically indicated, ProSobee, Lactofree, Alactamil, Nutramigen, or Pregestimil may be used in place of Enfamil or Enfalac with Iron. Term infants will receive at least 85% of their nutrition from breast milk. Primary measures of effectiveness will include visual acuity and red blood cell membrane fatty acid profiles (i.e. DHA and ARA levels). The measure of safety will be growth and adverse experience reports.
[0031] 2. SUBJECTS
[0032] 2.1 SOURCE AND CHARACTERIZATION OF STUDY GROUP
[0033] Acceptable preterm subjects will be relatively healthy premature infants taking preterm formula. Anticipated hospitalization should be sufficient to allow for 28 days of enteral intake ≧90 kcal/kg/d and ≧85% study formula intake. All races and both sexes will be eligible for the study.
[0034] 2.2 INCLUSION CRITERIA
[0035] Preterm infants
[0036] Birth weight ≧900 g
[0037] Formula feeding at time of study enrollment
[0038] Anticipate enteral intake of ≧90 kcal/kg/day for ≧28 days before discharge home
[0039] Informed consent obtained
[0040] Term Infants:
[0041] 38 to 42 weeks gestation
[0042] Committed to breast feeding
[0043] Informed Consent obtained
[0044] 2.3 EXCLUSION CRITERIA
[0045] Preterm infants
[0046] ≧1500 g at birth
[0047] Preterm and Term Infants:
[0048] History of underlying disease or congenital malformation which in the opinion of the investigator is likely to interfere with the evaluation of the subject
[0049] More than 24 days between birth and full oral feeds (≧90 kcal/kg/d)
[0050] Small (<10th percentile) for gestational age at birth (SGA)
[0051] Necrotizing enterocolitis as diagnosed by the physician
[0052] Other gastrointestinal disease
[0053] Impaired visual or ocular status at birth
[0054] 2.4 CONCOMITANT MEDICATIONS, HOSPITALIZATIONS, ILLNESSES
[0055] No medication which may effect FPL response may be used within 3 days of measurement.
[0056] No evidence of viral of bacterial infection during FPL testing.
[0057] No medications known to effect lipid metabolism (e.g., heparin at therapeutic levels)
[0058] 3. STUDY PRODUCT INFORMATION
[0059] 3.1 FORMULATIONS
[0060] Nutrient composition is included as Appendix A.
[0061] 4. STUDY PROCEDURES
[0062] 4.2.1 ENROLLMENT
[0063] Enrollment will take place over a 6 month period. Ideally, sufficient subjects will be enrolled so that 10 subjects in each group complete the study at each site for the multi-center trial. A total of 50 infants per formula group will complete this trial.
[0064] 4.2.2 SCHEDULE OF EVENTS (SEE FLOW CHART, SECTION 8.4)
[0065] 4.2.2.1 RECRUITMENT
[0066] Mothers of eligible, healthy, preterm formula fed infants and term, breastfed infants will be contacted, the study explained to them, and if they are agreeable, written informed consent obtained.
[0067] Term infants may be enrolled anytime from birth until or during the 48 week visit.
[0068] 4.2.2.2 RANDOMIZATION
[0069] Recruited formula fed subjects will be randomized into study groups. Randomization can occur anytime after enteral feeds reach 50 kcal/kg/day until commencement of full enteral feeds (i.e., ≧90 kcal/kg/day).
[0070] 4.2.2.3 FEEDING
[0071] All premature infants will receive their assigned study formula after informed consent has been granted and enteral feeds are at least 50 kcal/kg/day. The infant will remain on study formula 28 days after reaching 90 kcal/kg/d or until hospital discharge, whichever is longer. Oral feeding amount, strength and rate will advance as appropriate for the clinical management of the infant.
[0072] All parents will be instructed not to feed solid foods during the study.
[0073] The parents will be instructed that the study formula or breast milk is to serve as the sole source of food from enrollment to study end.
[0074] 4.2.2.4 BASELINE DATA COLLECTION
[0075] The following data will be collected by the Investigator at the time of enrollment and randomization on the case report forms:
[0076] Informed consent of parent obtained.
[0077] Post conceptual age.
[0078] That the subject is a premature infant, with Birth weight ≧900 gm and ≧1500 gm or a normal term infant between 38 and 42 weeks gestational age.
[0079] That the preterm subject is receiving infant formula or term infant is committed to breast feeding.
[0080] Anticipated preterm infant enteral intake of ≧90 kcal/kg/day for ≧28 days prior to discharge home.
[0081] That the subject has no history of underlying disease, inborn error of metabolism, or congenital malformation which in the opinion of the Investigator is likely to interfere with the evaluation of the study formulas.
[0082] That the subject is not small (<10th percentile) for gestational age at birth
[0083] That the subject does not have necrotizing enterocolitis as diagnosed by a physician.
[0084] That the subject does not have a gastrointestinal disease.
[0085] No more than 24 days between birth and full enteral feeds (i.e., ≧90 kcal/kg/day).
[0086] That the subject did not have impaired visual or ocular status at birth.
[0087] Birth date, sex, race.
[0088] Birth weight, length and head circumference
[0089] 4.2.2.5 INVESTIGATOR PERIODIC DATA COLLECTION
[0090] “During hospitalization, preterm subjects will have their weight recorded daily while they are receiving study formula Length and head circumference will be recorded weekly, along with an additional weight measurement. For a given subject, the same scale should be used for the weekly weight measurement.”
[0091] “Weight, length, and head circumference will also be recorded at the 40, 48, and 57 week post conceptual age visit (preterm) and 56 and 119 days of age visit (term).”
[0092] 4.2.2.6 BLOOD DRAW
[0093] When preterm infant enrolls in the study and again at termination of study formula (i.e., hospital discharge or 28 days after reaching 90 kcal/kg/d of study product), the Investigator will ascertain that the infant is essentially solely formula fed. If this criteria is met, 1.2 ml/blood will be drawn for blood lipids. The sample will be processed as described in Appendix B.
[0094] An attempt will also be made to draw a similar blood sample at the 48 weeks PCA visit when visual acuity is measured in both term and preterm infants.
[0095] 4.2.2.7 VISUAL ACUITY BY FORCED CHOICE PREFERENTIAL LOOKING (FPL) AT 48 AND 57 WEEKS±4 DAYS POST-CONCEPTUAL AGE
[0096] When the infant is 48 and 57 weeks±4 days post-conceptual age, trained persons at each study site will follow the Teller Acuity Card Procedure for the measurement of visual acuity of all study subjects. It is essential that only persons who are trained in the FPL procedure for determining visual acuity do the testing. If necessary, training of responsible persons and documentation of completion of successful training will be done at Children's Hospital Medical Center Ophthalmology Department in Seattle, Wash., according to the procedure attached as Appendix C.
[0097] If the infant cannot complete the procedure at 48 or 57 weeks±4 days postconceptual age (i.e., too fussy, too sleepy, too inattentive) the test should be repeated within 7 days.
[0098] 4.2.2.8 INTERIM EVALUATION
[0099] At preterm infant hospital discharge or 28 days after reaching 90 kcal/kg/d of study formula feeding, whichever is longer, the investigator will fill out an “Interim Evaluation” form. After reviewing the subject's records and discussion with the parents and staff, the investigator will indicate whether:
[0100] Whether or not the subject completed at least 28 days of study formula intake ≧90 kcal/kg/d and both blood samples obtained
[0101] If the study was not completed, and reason
[0102] Whether or not the subject received steroids (glucorticoids)
[0103] Investigator's evaluation of the study formula
[0104] The first and last dates study material was taken will be recorded.
[0105] 4.2.2.9 FINAL EVALUATION
[0106] At the final study visit (57 weeks postconceptual age) or earlier if the subject drops out, the Investigator will fill out a “Final Evaluation” Case Report Form. After reviewing the subject's records and discussion with the parents, the Investigator will indicate whether the subject:
[0107] (1) Completed feeding regiment and all study parameters (i.e., anthropometrics and visual acuity measured).
[0108] (2) Did not complete feeding regimen.
[0109] (3) Not completed and reason.
[0110] 4.3 CLINICAL OBSERVATIONS
[0111] 4.3.1 PHYSICAL EXAMINATIONS
[0112] Subjects will have weight, length and head circumferences recorded at birth, weekly while hospitalized, then at 40, 48, and 57 weeks±4 days postconceptual age.
[0113] Body weight will be measured using an electronic balance or a double beam balance accurate to 10 g or ½ oz with non-detachable weights. During hospitalization, if more than one such balance is employed in the practice, either one balance should be designated the study balance and all study weights will be carried out on that balance for a particular subject, or the balances will be checked and certified to register the same weight throughout the range of weights expected. Outpatient weights will be obtained on a calibrated office scale.
[0114] Documentation indicating balance calibration of the outpatient balance carried out within 12 months of study initiation will be supplied to the Sponsor.
[0115] Length will be measured with the infant in recumbent position with the help of two examiners and a suitable measuring apparatus. One person holds the subject's head in contact with a fixed vertical headboard and a second person holds the subject's feet, toes pointing directly upward and, also applying gentle traction. The baby is measured from the headboard to the soles of the feet with a non-stretching tape measure.
[0116] Head circumference will be measured, employing a flexible, non-stretchable cloth or vinyl tape.
[0117] 4.3.2 VISUAL ACUITY BY FORCED CHOICE PREFERENTIAL LOOKING (FPL)
[0118] Visual acuity will be determined at 48 and 57 weeks±4 days postconceptual age according to procedures outlined in Appendix C.
[0119] 4.3.3 LABORATORY TESTS
[0120] Blood will be drawn from preterm infants by heel prick or venipuncture when study formula is begun and terminated. An attempt will be made to draw blood at 48 weeks±4 days PCA from both term and preterm infants. Procedures for handling the blood are described in Appendix B.
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FLOW CHART 4.4
PRETERMTERM
EnteralTerminationVisit 1Visit 2Visit 3Visit 1Visit 2Visit 3
Intake > 50of Study40 wks ± 4d48 wks ± 4d57 wks ± 4d40 wks ± 4d48 wks ± 4d57 wks ± 4d
EVENTBirthkcal/kg/dFormula †PCAPCAPCAPCAPCAPCA
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Randomization✓
Study Formula✓
Enfamil w/iron✓✓✓✓
Human Milk✓✓✓
PhysicalPhysical
Weight✓✓*✓✓✓✓✓✓✓
Length✓✓*✓✓✓✓✓✓✓
Head✓✓*✓✓✓✓✓✓✓
Circumference
Blood Draw✓✓✓✓
Visual Acuity✓✓✓✓
Test
Illnesses✓✓✓✓
Interim✓
Assessment
Final(when the sublect discontinues or completes)(when the sublect discontinues or
completes)
Assessment
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✓Medical problems related to or affecting formula consumption will be recorded when they occur.
*daily and weekly during hospitalization.
†At hospital discharge or 28 days of study formula intake (after reaching 90 kcal/kg/d), whichever ss later.
[0121] 5. CRITERIA FOR RESPONSE
[0122] Criteria for response will depend upon the following:
[0123] Visual Acuity better than the control formula.
[0124] Visual Acuity comparable to breastfed term infant.
[0125] Red Blood Cell phosphatidyl ethanolamine DHA and ARA weight % greater than formula control group.
[0126] Growth as measured by weight achieved at 48 and 57 weeks postconceptual age comparable to formula control group.
[0127] 6. STATISTICS
[0128] 6.1 RANDOMIZATION
[0129] If the subject meets the inclusion and exclusion criteria, randomization to one of three formula groups will take place. The randomization schedule will be provided by Mead Johnson Research Center. A separate randomization schedule will be provided for males and females.
[0130] 6.2 SAMPLE SIZE
[0131] The primary parameter of interest is visual acuity as measured by the Forced Choice Preferential Looking (FPL). The minimal clinically relevant difference was determined to be 0.5 octave. A consultant in the field of visual acuity estimated the standard deviation to be 0.5 octave. This value was increased to .7 octave in case more variability was experienced in this study. Thirty-two subjects per group are needed to attain 80% power when testing at an alpha level of 0.05.
[0132] A sample size estimate of 50 per group was determined to achieve α+0.05, β+0.20, for weight of infants receiving study oil being greater than 400 gm below control at 48 weeks postconceptual age or 500 g below control at 57 weeks postconceptual age with a standard deviation of 800 g. It was therefore determined that 50 subjects per group will be used in the study.
[0133] 6.3 ANALYTICAL PLAN
[0134] Visual acuity data will be recorded in cycles per cm. These values will be converted to cycles per degree using the following formula:
1
[0135] A log transformation will be applied to the data prior to analysis. Analysis of variance techniques will be used to assess feeding regimen group differences in visual acuity. If the overall F test for feeding regimen is significant at al alpha level of 0.05, pairwise comparisons will be made at an alpha level of 0.05. If no significant differences are detected, then a post-study power analysis will be performed to demonstrate that the study had adequate power to detect the minimal clinically relevant difference.
[0136] Analysis of variance will be used to assess feeding regimen differences in phosphatidyl choline DHA and ARA levels and in phosphatidyl ethanolamine DHA and ARA levels at each time point. If the overall F test is significant at al alpha level of 0.05, then pairwise comparisons will be made at an alpha level of 0.05.
[0137] Analysis of variance will be used to assess feeding regiment differences in weight at 48 and 57 weeks postconceptual age. The statistical model will include terms for feeding regimen, study center, sex and all two-way interactions. Non-significant interactions will be removed from the final statistical model. Two one-sided tests will be performed comparing each experimental formula (EC) with the control formula (CF). The hypothesis to be tested is as follows:
H0=Weight (CF)≦Weight (EF).
[0138] The alternative hypothesis is as follows:
H1=Weight (CF)>Weight (EF).
[0139] If H0 if rejected and the mean weight of the control formula exceeds that of the experimental formula by more than 400 mg at 48 weeks postconceptual age or by 500 g at 57 weeks postconceptual age then the conclusion is that the experimental formula does not exceed that of the experimental formula by more than 400 g at 48 weeks postconceptual age or by 500 mg at 57 weeks postconceptual age then the conclusion is that the experimental formula does provide adequate growth. If H0 is not rejected then a post-study power analysis will be performed to demonstrate that eh study had adequate power to detect the above mentioned clinically relevant differences. If adequate power is achieved then the conclusion is that the experimental formula does provide adequate growth.
[0140] Fisher's exact test will be used to compare the proportion of subjects in each group with illness/symptoms of concern during the study. The analysis will be performed for each type of illness/symptom reported, with classification of investigator terms into similar terminology made as necessary.
2APPENDIX A
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NUTRIENT COMPOSITION OF FORMULAS
All study formulas are 24 kcal/fl oz and are identical in composition
to marketed Enfamil Premature Formula except for the study oils
employed. These oils are described in the protocol.
STUDY FORMULAS
NUTRIENTAMOUNT/100 kcalENFAMIL WITH Fe
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Protein, g32.2
Fat, g5.15.6
Carbohydrate, g11.110.3
Vitamin A IU1250310
Vitamin D IU27063
Vitamin E IU6.32
Vitamin K mcg88
Thiamine, mcg20078
Riboflavin, mcg300150
Vitamin B4, mcg15063
Vitamin B12, mcg0.250.23
Niacin, mcg40001250
Folic Acid, mcg3515.6
Pantothenate, mcg1200470
Biotin, mcg42.3
Vitamin C, mg208.1
Choline, mg1215.6
Inositol, mg174.7
Calcium, mg16578
Phosphorus, mg8353
Magnesium, mg6.37.8
Iron, mg1.80.5
Zinc, mg1.50.78
Manganese, mcg6.315.6
Copper, mcg12594
Iodine, mcg256
Sodium mg (mEq)39 (1.7)27 (1.17)
Potassium mg (Meq)103 (2.6)108 (2.5)
Chloride mg (Meq)85 (2.4)63 (177)
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FINAL STUDY REPORT
[0141] Study Design: This double-blind, parallel-group study (project 3338) was carried out in 16 neonatal centers (study numbers 9698-9709, 9712, 9723, 9743, and 9746) in North America. Three premature infant feedings were compared. Each had the same composition except for the incorporation of fungal and/or micro algal oils up to about 3% of the fat blend to provide the experimental levels of docosahexaenoic acid (DHA) and arachidonic acid (ARA). The control formula (C, Enfamil® Premature Formula) contained no DHA or ARA, the DHA formula (D) contained about 0.15% of energy as DHA (0.34% of fat), and the DHA+ARA formula (DA) contained about 0.14% of energy as DHA (0.33% of fat) and 0.27% of energy as ARA (0.60% of fat). The formulas were fed to 284 randomized infants weighing 846 to 1560 grams at birth for at least 28 days. Upon completion of study formula intake, they were given routine infant formula and followed through 4 months gestationally corrected age. A group of 90 exclusively human milk fed term infants were enrolled and followed to 4 months of age as a reference group (H).
[0142] Study Objective and Statistical Analysis: The primary objective of this study was to establish the safety of feeding D or DA to preterm infants during their initial hospitalization as measured 1) by growth, acceptance and tolerance while consuming the formula for at least 1 month and 2) by close monitoring and observation for a 4 to 5 month follow-up period (4-5 times the treatment period) while consuming unsupplemented routine term infant formula. The primary growth parameter selected was weight with evaluation of the proposition that weight on test formula was greater than or equal to weight on control formula. The one sided statistical test for an adverse effect on growth maximized the power to detect a difference should one be present. A two-sided test was used for all other parameters. A p-value of less than 0.05 was used to establish significance.
[0143] Secondary objectives of the study were 1) to evaluate the impact of fatty acid levels in erythrocyte phospholipids at the end of study feeding and 2) to determine if any effect on mean visual acuity greater than half an octave could be demonstrated at 2 and 4 months corrected age.
[0144] Results: Six infants were just outside the weight parameters and five infants just older than the less than 24 days chronological age parameter for enrollment in the study. In each case, judgement by the clinical or medical monitor was made to include them in the study prior to enrollment based on their homogeneity with other study infants in all other particulars, e.g., state of health, type of medical complications, and weight for gestational age. All these infants were included in the analysis of the study results.
[0145] The formula groups were comparable at enrollment (See table 1). Post-conceptual age, weight, length, and head circumference at enrollment did not differ among the groups.
[0146] All groups experienced comparable final study status (See table 2). Drop outs did not differ among the formula fed groups during hospitalization. There also were no differences in drop outs among the four groups at study completion.
[0147] Both formulas D and DA provide adequate growth when compared to formula C (See table 3, FIG. 1, and Appendix 1). Weight gain during hospitalization was no less on D or DA than on C, 33.3, 34.7, and 30.7 g/day, respectively. Furthermore, no less weight was achieved on D or DA than on C at 40, 48, and 57 weeks post-conceptual age (See table 4, FIG. 2, and Appendix 1); statistical power was greater than 0.89 to detect a clinically relevant decrease.
[0148] Post-hoc analysis reveals that infants on DA grew faster than infants receiving C and D (See table 5 and FIG. 1). This enhanced growth provided faster “premature infant catch-up” compared to C and D. Weight achieved by the DA group (3198 g) was higher than C (3075 g) and D (3051 g) at 40 weeks post-conceptual age but had not fully caught up to the term birth weight (3438 g) of group H (See table 4 and FIG. 2). This catch up trend continued through 48 to 57 weeks by which time the mean weight of group DA did not differ from group H while groups C and D remained significantly lower.
[0149] Length was not different among the formula groups either during hospitalization or the follow-up period, although the ordered sequence of mean lengths was the same as for the weights (See table 7 and FIG. 3). This is likely at least partially due to length being a less sensitive parameter of growth than weight. For the same reason, the mean lengths of group H infants were higher than that of all the premature infant groups at 40, 48 and 57 weeks post-conceptual age indicating slower catch up in this parameter.
[0150] Head circumference is the least sensitive parameter of growth and was not different among any of the four groups at any time measured except at 40 weeks postconceptual age (See table 8 and FIG. 4). At this time, as expected, the birth head circumference of group H was smaller than the formula fed premature infants possibly due to molding of labor and to insufficient time for adjustment to the extrauterine environment.
[0151] Visual acuity has reportedly been enhanced in studies where DHA supplemented formulas were fed to premature infants both in the hospital and continuing after discharge. In this study, visual acuity was measured about 3 months and then about 5 months after stopping study formula to determine whether a residual beneficial effect of at least half an octave might be observed. Although no difference in visual acuity was found among the formula groups at these times (See table 8 and FIG. 5), the acuity card method used, the length of study formula feeding, and/or the length of time not on study formula at the time of measurement may have precluded its detection. However, at 57 weeks post-conceptual age, the breast fed term infant group did have statistically higher visual acuity scores than the test formula groups. But even these differences were at most only 0.33 octave and were clinically insignificant (See FIG. 6). It is important to note that the breast fed infants continued to receive DHA and ARA during the 3-5 month follow-up period while the formula fed groups did not. Thus, this minor difference in performance was not unexpected based on previous study findings and on developmental differences between term and preterm infants even at the same gestational age.
[0152] Individual fatty acid levels were determined in the phosphatidylcholine and phosphatidylethanolamine fractions of red blood cells before formula feeding, at the conclusion of test formula feeding, and at 48 weeks post-conceptual age (See tables 9 and 10). The premature infant groups were comparable at the beginning of test formula feeding. At the conclusion of test formula feeding, individual fatty acid levels varied among the groups. DHA and ARA were statistically significantly higher in the respectively supplemented groups. Other fatty acid levels reflected the impact of the supplementation. No clinically significant alterations in fatty acid levels or metabolism were identified. After discontinuing study formula and consuming a diet without DHA or ARA for about 3 months, no differences in fatty acid levels among formula fed groups were detectable, except for phosphatidylethanolamine levels of 18:2 (range 8.9-9.3%) and DHA (range 3.2-4.1%) which differences were not identified as being clinically significant. However, the breast fed group shows statistically significant differences in 13 fatty acid levels compared to the formula fed infants. These differences are undoubtedly due to the differences in fatty acid composition of human milk and the term formulas including the lack of DHA and ARA in the latter.
[0153] Preterm infant complications were similar in all groups (See table 11). Over 80% of all infants were ophthamologically examined and over 90% had ultrasound evaluation of their heads. Specifically, the incidence and severity of retinopathy of prematurity (ROP or retrolental fibroplasia/RLF) and the incidence of intraventricular hemorrhage or its complications did not differ among formula groups. No feeding group related complications were identified.
[0154] Serious adverse experiences did not differ (p=0.93) among the formula groups and were in the range of those expected in a premature infant population while on study formula: 6% in group C, 5% in group D, and 6% in group DA (See table 12). After the experimental formula phase, serious adverse experiences still did not differ among the preterm groups (See table 13): 13% in group C, 15% in group D, and 15% in group DA. However, the term infant breast fed group had significantly fewer serious adverse experiences (1%, p=0.002) as expected. Two infants reportedly suffered sudden infant death syndrome (SIDS), one in group C and one in group D; there was no significant difference in this complication among all four groups.
[0155] Conclusions: We conclude that feeding 0.13% of calories as DHA from micro algal oil and feeding 0.13 % of calories as DHA from micro algal oil plus 0.26% of calories as ARA from fungal oil in the matrix of premature infant formula to premature infants during the period of their initial hospitalization prior to 40 weeks post conceptual age is safe. These micro algal and fungal oil supplements do not result in any adverse effect on growth, clinical complications, or untoward events. Furthermore, this study reveals that growth benefits accrue to premature infants fed Enfamil Premature Formula supplemented with DHA and ARA from these sources compared to unsupplemented formula or formula supplemented with only DHA. No measurable benefit on visual acuity was identified when infants were tested at about 3 and 5 months after the supplemented formula was discontinued (2 and 4 months corrected age). However, providing human milk levels of intake of long chain polyunsaturated acids are warranted because they are critical to brain development and foster enhanced catch-up growth during this early development period.
3TABLE 1
|
|
Birth Statistics of Premature Subjects
nMean (std)Rangep-value
|
Post-Conceptual
Age (Weeks)
Control6229.5 (1.7)25-330.076
DHA6630.0 (1.4)26-32
DHA + ARA6629.7 (1.7)26-34
Birth Weight (g)
Control621233.1 (176.6) 846-15600.25
DHA661272.8 (168.1) 900-1545
DHA + ARA661278.9 (177.6) 910-1535
Birth Length (cm)
Control6038.4 (2.3) 34-43.750.62
DHA6638.6 (2.2) 33-43.5
DHA + ARA6638.7 (2.3)33-44
Birth Head
Circumference (cm)
Control6126.9 (1.5)23.5-30.50.53
DHA6427.3 (2.1)22-37
DHA + ARA6527.2 (1.6)23.5-30
|
[0156]
4
TABLE 2
|
|
|
Summary of Final Study Status
|
Regimen
|
Control
DHA
DHA + ARA
HM
p-value
|
|
Immediate dropout, study formula
2
2
|
never consumed
|
Study Formula Phase*
|
Completed
52 (84%)
59 (89%)
62 (94%)
0.20
|
Discontinued
10 (16%)
7 (11%)
4 (6%)
|
Reason discontinued
|
>96 cumulative hours NPO
3
1
|
<28 days of intake ≧ 90 kcal/kg/day
3
3
|
Complications unrelated to study
1
|
formula
|
NEC or other GI
1
1
|
disease
|
Formula intolerance
1
|
Parents request
2
2
1
|
Not off oxygen prior
1
|
to discharge
|
Protocol violation
1
|
Term Formula
|
Phase **
|
Completed
45 (87%)
47 (80%)
53 (85%)
77 (86%)
0.74
|
Discontinued
7 (13%)
12 (20%)
9 (15%)
13 (14%)
|
|
*The CRFs for 9709-003 (DHA) and 9743-304 (DHA) were marked discontinued because the subjects met the study formula intake criteria for only 27 days. These subjects are counted completed here because subjects at other sites with similar intakes were marked completed.
|
**Based on subjects who completed the Study Formula phase. During the Term Formula phase, subjects were fed marketed formula. Switching to a different marketed formula did not result in termination from the Term Formula phase.
|
[0157]
5
TABLE 3
|
|
|
Weight Growth Rate During Study Formula Phase
|
Least Square
Standard
Comparison
Study
Gender
Gender-by-Regimen
|
Regimen
n
Mean
Error
Comparison
p-value*
p-value
p-value
p-value
|
|
Control
60
30.7
1.1
Control vs DHA
0.967
0.00
0.17
0.87
|
DHA
65
33.3
1.1
Control vs DHA + ARA
0.998
|
DHA + ARA
66
34.7
1.1
|
|
*One-sided test of the null hypothesis: Test Hean ≧ Control Mean
|
[0158]
6
TABLE 4
|
|
|
Weight at 40, 48, and 57 Weeks Post-Conceptual Age
|
Weeks
Least
|
Post-Conceptual
Square
Standard
Comparison
Study
Gender
Gender-by-Regimen
|
Age
Regimen
n
Mean
Error
Comparison
p-value*
p-value
p-value
p-value
|
|
40
Control
52
3075.3
67.9
Control vs DHA
0.388
0.59
0.45
1.00
|
DHA
54
3051.4
66.8
Control vs DHA + ARA
0.931
|
DHA + ARA
59
3198.2
62.9
HM vs DHA
0.000
|
HM
90
3437.7
60.6
HM vs DHA + ARA
0.001
|
HM vs Control
0.000
|
48
Control
53
4711.0
94.6
Control vs DHA
0.360
0.58
0.13
0.29
|
DHA
51
4663.8
97.3
Control vs DHA + ARA
0.995
|
DHA + ARA
57
5039.1
93.0
HM vs DHA
0.000
|
HM
81
5181.5
85.9
HM vs DHA + ARA
0.114
|
HM vs Control
0.000
|
57
Control
47
6045.4
139.5
Control vs DHA
0.371
0.58
0.29
0.33
|
DHA
49
5987.2
137.6
Control vs DHA + ARA
0.940
|
DHA + ARA
55
6312.9
127.9
HM vs DHA
0.005
|
HM
76
6405.0
126.7
HM vs DHA + ARA
0.278
|
HM vs Control
0.014
|
|
*one-sided test of the null hypothesis: Test Mean ≧ Control Mean
|
[0159]
7
TABLE 5
|
|
|
Post-hoc Analysis of Weight
|
Two-sided
|
Time
Comparison
p-value
|
|
Weight Gain During Study
C vs. DHA
0.067
|
Formula Phase
C vs. DHA + ARA
0.004
|
DHA vs. DHA + ARA
0.30
|
Weight at 40 Weeks pca
C vs. DHA
0.78
|
C vs. DHA + ARA
0.14
|
DHA vs. DHA + ARA
0.074
|
HM vs. DHA
<0.001
|
HM vs. DHA + ARA
0.002
|
HM vs. C
<0.001
|
Weight at 48 Weeks pca
C vs. DHA
0.72
|
C vs. DHA + ARA
0.011
|
DHA vs. DHA + ARA
0.004
|
HM vs. DHA
<0.001
|
HM vs. DHA + ARA
0.23
|
HM vs. C
<0.001
|
Weight at 57 Weeks pca
C vs. DHA
0.74
|
C vs. DHA + ARA
0.12
|
DHA vs. DHA + ARA
0.057
|
HM vs. DHA
0.010
|
HM vs. DHA + ARA
0.56
|
HM vs. C
0.028
|
|
[0160]
8
TABLE 6
|
|
|
Length at 40, 48, and 57 Weeks Post-Conceptual Age
|
Weeks
Least
Gender-by-
|
Post-Conceptual
Square
Standard
Regimen
Pairwise
Pairwise
Study
Gender
Regimen
|
Age
Regimen
n
Mean
Error
p-value
Comparison
p-value
p-value
p-value
p-value
|
|
40
Control
52
48.4
0.4
0.000
Control vs DHA
0.242
0.03
0.88
0.63
|
DHA
54
47.8
0.4
Control vs DHA + ARA
0.233
|
DHA + ARA
58
49.0
0.4
HM vs DHA
0.000
|
HM
89
50.6
0.4
HM vs DHA + ARA
0.000
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.017
|
48
Control
53
54.7
0.3
0.000
Control vs DHA
0.824
0.00
0.14
0.52
|
DHA
52
54.6
0.3
Control vs DHA + ARA
0.079
|
DHA + ARA
57
55.5
0.3
HM vs DHA
0.000
|
HM
81
57.4
0.3
HM vs DHA + ARA
0.000
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.050
|
57
Control
47
60.7
0.4
0.000
Control vs HM
0.615
0.00
0.02
0.84
|
DHA
49
60.5
0.4
Control vs DHA + ARA
0.236
|
DHA + ARA
54
61.5
0.3
HM vs DHA
0.000
|
HM
76
62.4
0.3
HM vs DHA + ARA
0.006
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.087
|
|
[0161]
9
TABLE 7
|
|
|
Head Circumference at 40, 48, and 57 Weeks Post-Conceptual Age
|
Weeks
Least
Gender-by-
|
Post-Conceptual
Square
Standard
Regimen
Pairwise
Pairwise
Study
Gender
Regimen
|
Age
Regimen
n
Mean
Error
p-value
Comparison
p-value
p-value
p-value
p-value
|
|
40
Control
51
35.4
0.2
0.000
Control vs DHA
0.931
0.91
0.00
0.38
|
DHA
53
35.4
0.2
Control vs DHA + ARA
0.900
|
DHA + ARA
58
35.4
0.2
HM vs DHA
0.000
|
HM
85
34.5
0.2
HM vs DHA + ARA
0.000
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.829
|
48
Control
52
39.1
0.2
0.983
0.81
0.00
1.00
|
DHA
51
39.0
0.2
|
DHA + ARA
56
39.0
0.2
|
HM
81
39.0
0.1
|
|
|
57
Control
47
41.9
0.2
0.689
0.64
0.00
0.85
|
DHA
49
41.6
0.2
|
DHA + ARA
53
41.7
0.2
|
HM
76
41.7
0.2
|
|
[0162]
10
TABLE 8
|
|
|
Visual Acuity at 48 and 57 Weeks Post-Conceptual Age
|
Weeks
Geometric
Least Square
Standard
|
Post-Conceptual
mean
Mean (log base2
Error
Regimen
Pairwise
Pairwise
Study
|
Age
Regimen
n
(cycles/deg)
cycles/deg)
(octaves)
p-value
Comparison
p-value
p-value
|
|
48
ControL
51
1.72
0.78
0.10
0.950
0.000
|
DHA
50
1.80
0.85
0.10
|
DHA + ARA
57
1.72
0.78
0.09
|
HM
81
1.75
0.81
0.09
|
57
Control
46
3.47
1.79
0.08
0.004
Control vs DHA
0.697
0.000
|
DHA
47
3.37
1.75
0.08
Control vs DHA + ARA
0.071
|
DHA + ARA
55
3.06
1.61
0.07
HM vs DHA
0.042
|
HM
77
3.85
1.94
0.07
HM vs DHA + ARA
0.000
|
Control vs HM
0.113
|
DHA vs DHA + ARA
0.158
|
|
[0163]
11
TABLE 9
|
|
|
Red Blood Cell phosphatidylcholine Fatty Acids
|
Fatty
Arithmetic
Standard
Regimen
Pairwise
Pairwise
|
Time
Acid
Regimen
n
Mean
Error
Median
p-value
Comparison
p-value
|
|
Study Form Initiation
12:0
Control
52
0.081
0.019
0.036
0.762
|
DHA
58
0.066
0.013
0.030
|
DHA + ARA
61
0.057
0.009
0.031
|
Study Form Initiation
14:0
Control
52
0.623
0.036
0.599
0.559
|
DHA
58
0.663
0.031
0.686
|
DHA + ARA
61
0.661
0.031
0.656
|
Study Form Initiation
14:1
Control
52
0.045
0.009
0.021
0.165
|
DHA
58
0.026
0.005
0.016
|
DHA + ARA
61
0.035
0.006
0.018
|
Study Form Initiation
16:0
Control
52
36.706
0.540
36.594
0.884
|
DHA
58
36.363
0.462
35.578
|
DHA + ARA
61
36.877
0.445
35.987
|
Study Form Initiation
16:1
Control
52
0.940
0.049
0.845
0.441
|
DHA
58
0.981
0.050
0.976
|
DHA + ARA
61
1.094
0.064
0.931
|
Study Form Initiation
18:0
Control
52
11.660
0.243
11.468
0.243
|
DHA
58
11.402
0.238
11.201
|
DHA + ARA
61
11.016
0.192
11.174
|
Study Form Initiation
18:1
Control
52
17.053
0.298
17.308
0.679
|
DHA
58
17.219
0.391
16.935
|
DHA + ARA
61
17.256
0.271
16.988
|
Study Form Initiation
18:2
Control
52
18.614
0.525
18.952
0.830
|
DHA
58
18.631
0.505
19.603
|
DHA + ARA
61
18.573
0.466
18.824
|
Study Form Initiation
18:3n6
Control
52
0.120
0.008
0.116
0.034
Control vs DHA
0.196
|
DHA
58
0.136
0.008
0.130
Control vs DHA + ARA
0.010
|
DHA + ARA
61
0.150
0.009
0.134
DHA vs DHA + ARA
0.176
|
Study Form Initiation
20:0
Control
52
0.399
0.050
0.224
0.647
|
DHA
58
0.337
0.035
0.236
|
DHA + ARA
61
0.310
0.037
0.188
|
Study Form Initiation
18:3n3
Control
52
0.315
0.033
0.246
0.234
|
DHA
58
0.257
0.014
0.246
|
DHA + ARA
61
0.233
0.010
0.216
|
Study Form Initiation
20:1
Control
52
0.287
0.020
0.262
0.723
|
DHA
58
0.287
0.015
0.281
|
DHA + ARA
61
0.268
0.011
0.269
|
Study Form Initiation
18:4
Control
52
0.017
0.003
0.000
0.290
|
DHA
58
0.025
0.004
0.017
|
DHA + ARA
61
0.017
0.003
0.008
|
Study Form Initiation
20:2n6
Control
52
0.632
0.025
0.632
0.673
|
DHA
58
0.628
0.025
0.640
|
DHA + ARA
61
0.602
0.021
0.614
|
Study Form Initiation
20:3n6
Control
52
2.144
0.098
2.096
0.507
|
DHA
58
2.208
0.080
2.296
|
DHA + ARA
61
2.218
0.074
2.135
|
Study Form Initiation
20:4n6
Control
52
7.657
0.262
8.124
0.819
|
DHA
58
8.164
0.347
7.876
|
DHA + ARA
61
8.090
0.310
8.207
|
Study Form Initiation
22:1
Control
52
0.106
0.010
0.105
0.155
|
DHA
58
0.127
0.010
0.130
|
DHA + ARA
61
0.126
0.010
0.139
|
Study Form Initiation
20:5n3
Control
52
0.351
0.057
0.298
0.911
|
DHA
58
0.322
0.015
0.302
|
DHA + ARA
61
0.321
0.015
0.329
|
Study Form Initiation
22:4n6
Control
52
0.578
0.144
0.423
0.331
|
DHA
58
0.493
0.030
0.481
|
DHA + ARA
61
0.443
0.021
0.425
|
Study Form Initiation
24:1
Control
52
0.208
0.054
0.075
0.665
|
DHA
58
0.115
0.019
0.084
|
DHA + ARA
61
0.180
0.056
0.096
|
Study Form Initiation
22:5n6
Control
52
0.266
0.020
0.232
0.923
|
DHA
58
0.259
0.017
0.239
|
DHA + ARA
61
0.265
0.018
0.256
|
Study Form Initiation
22:4n3
Control
52
0.000
0.000
0.000
0.199
|
DHA
58
0.001
0.001
0.000
|
DHA + ARA
61
0.002
0.001
0.000
|
Study form Initiation
22:5n3
Control
52
0.213
0.019
0.203
0.885
|
DHA
58
0.215
0.013
0.195
|
DHA + ARA
61
0.203
0.010
0.193
|
Study Form Initiation
22:6n3
Control
52
0.984
0.051
1.000
0.858
|
DHA
58
1.075
0.053
1.034
|
DHA + ARA
61
1.006
0.050
0.970
|
Study Form Termination
12:0
Control
53
0.100
0.026
0.035
0.843
|
DHA
56
0.111
0.042
0.031
|
DHA + ARA
59
0.064
0.012
0.032
|
Study Form Termination
14:0
Control
53
0.808
0.039
0.806
0.834
|
DHA
56
0.781
0.035
0.783
|
DHA + ARA
59
0.755
0.036
0.758
|
Study Form Termination
14:1
Control
53
0.047
0.008
0.033
0.155
|
DHA
56
0.036
0.009
0.015
|
DHA + ARA
59
0.036
0.007
0.018
|
Study Form Termination
16:0
Control
53
35.837
0.512
34.798
0.767
|
DHA
56
35.560
0.595
34.841
|
DHA + ARA
59
35.069
0.584
33.890
|
Study Form Termination
16:1
Control
53
0.566
0.026
0.526
0.013
Control vs DHA
0.118
|
DHA
56
0.594
0.042
0.475
Control vs DHA + ARA
0.003
|
DHA + ARA
59
0.526
0.029
0.472
DHA vs DHA + ARA
0.152
|
Study Form Termination
18:0
Control
53
13.972
0.261
14.197
0.886
|
DHA
56
14.065
0.237
13.867
|
DHA + ARA
59
14.341
0.253
14.108
|
Study Form Termination
18:1
Control
53
14.456
0.277
14.291
0.686
|
DHA
56
14.116
0.272
13.998
|
DHA + ARA
59
14.344
0.380
14.218
|
Study Form Termination
18:2
Control
53
21.673
0.340
21.506
0.001
Control vs DHA
0.600
|
DHA
56
22.045
0.457
22.517
Control vs DHA + ARA
0.005
|
DHA + ARA
59
19.899
0.337
20.662
DHA vs DHA + ARA
0.001
|
Study Form Termination
18:3n6
Control
53
0.080
0.006
0.074
0.527
|
DHA
56
0.088
0.009
0.076
|
DHA + ARA
59
0.087
0.013
0.066
|
Study Form Termination
20:0
Control
53
0.504
0.050
0.392
0.424
|
DHA
56
0.472
0.053
0.281
|
DHA + ARA
59
0.430
0.049
0.251
|
Study Form Termination
18:3n3
Control
53
0.321
0.020
0.283
0.031
Control vs DHA
0.503
|
DHA
56
0.335
0.030
0.285
Control vs DHA + ARA
0.068
|
DHA + ARA
59
0.273
0.009
0.256
DHA vs DHA + ARA
0.011
|
Study Form Termination
20:1
Control
53
0.318
0.014
0.302
0.149
|
DHA
56
0.300
0.013
0.283
|
DHA + ARA
59
0.307
0.013
0.283
|
Study Form Termination
18:4
Control
53
0.022
0.004
0.015
0.672
|
DHA
56
0.022
0.003
0.018
|
DHA + ARA
59
0.014
0.002
0.008
|
Study Form Termination
20:2n6
Control
53
0.893
0.026
0.910
0.051
|
DHA
56
0.880
0.023
0.873
|
DHA + ARA
59
0.824
0.022
0.821
|
Study Form Termination
20:3n6
Control
53
2.032
0.073
2.091
0.208
|
DHA
56
2.017
0.070
2.043
|
DHA + ARA
59
1.908
0.064
1.904
|
Study Form Termination
20:4n6
Control
53
6.046
0.240
6.029
0.000
Control vs DHA
0.097
|
DHA
56
5.774
0.220
5.892
Control vs DHA + ARA
0.000
|
DHA + ARA
59
8.465
0.255
8.891
DHA vs DHA + ARA
0.000
|
Study Form Termination
22:1
Control
53
0.117
0.010
0.125
0.946
|
DHA
56
0.110
0.009
0.114
|
DHA + ARA
59
0.115
0.011
0.104
|
Study Form Termination
20:5n3
Control
53
0.214
0.022
0.189
0.000
Control vs DHA
0.004
|
DHA
56
0.246
0.012
0.233
Control vs DHA + ARA
0.108
|
DHA + ARA
59
0.186
0.014
0.169
DHA vs DHA + ARA
0.000
|
study Form Termination
22:4n6
Control
53
0.484
0.048
0.390
0.093
|
DHA
56
0.489
0.061
0.462
|
DHA + ARA
59
0.496
0.027
0.487
|
Study Form Termination
24:1
Control
53
0.127
0.039
0.062
0.303
|
DHA
56
0.143
0.036
0.086
|
DHA + ARA
59
0.177
0.040
0.089
|
Study Form Termination
22:5n6
Control
53
0.181
0.181
0.163
0.006
Control vs DHA
0.005
|
DHA
56
0.145
0.001
0.133
Control vs DHA + ARA
0.895
|
DHA + ARA
59
0.172
0.009
0.165
DHA vs DHA + ARA
0.006
|
Study Form Termination
22:4n3
Control
53
0.001
0.001
0.000
0.359
|
DHA
56
0.001
0.001
0.000
|
DHA + ARA
59
0.003
0.002
0.000
|
Study Form Termination
22:5n3
Control
53
0.306
0.019
0.289
0.221
|
DHA
56
0.293
0.026
0.260
|
DHA + ARA
59
0.265
0.013
0.255
|
Study Form Termination
22:6n3
Control
53
0.895
0.072
0.812
0.000
Control vs DHA
0.000
|
DHA
56
1.380
0.063
1.352
Control vs DHA + ARA
0.000
|
DHA + ARA
59
1.244
0.049
1.259
DHA vs DHA + ARA
0.141
|
48 Weeks PCA
12:0
Control
37
0.032
0.005
0.026
0.729
|
DHA
32
0.028
0.006
0.016
|
DHA ARA
38
0.026
0.004
0.020
|
HM
56
0.059
0.016
0.020
|
48 Weeks PCA
14:0
Control
37
0.402
0.039
0.331
0.943
|
DHA
32
0.353
0.032
0.324
|
DHA ARA
38
0.353
0.024
0.328
|
HM
56
0.381
0.026
0.335
|
48 Weeks PCA
14:1
Control
37
0.025
0.006
0.013
0.448
|
DHA
32
0.026
0.007
0.011
|
DNA + ARA
38
0.026
0.006
0.015
|
HM
56
0.024
0.003
0.020
|
48 Weeks PCA
16:0
Control
37
34.627
0.577
34.319
0.000
Control vs DHA
0.527
|
DHA
32
35.272
0.689
34.473
Control vs DHA + ARA
0.593
|
DHA + ARA
38
34.802
0.506
34.165
HM vs DHA
0.000
|
HM
56
33.037
0.506
32.228
HM vs DHA + ARA
0.000
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.906
|
48 Weeks PCA
16:1
Control
37
0.435
0.043
0.338
0.000
Control vs DHA
0.524
|
DHA
32
0.380
0.023
0.352
Control vs DHA + ARA
0.467
|
DHA + ARA
38
0.395
0.024
0.368
HM vs DHA
0.000
|
HM
56
0.507
0.020
0.473
HM vs DHA + ARA
0.006
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.183
|
48 Weeks PCA
18:0
Control
37
13.016
0.313
12.759
0.000
Control vs DHA
0.760
|
DHA
32
12.944
0.249
12.786
Control vs DHA + ARA
0.889
|
DHA + ARA
38
12.804
0.235
12.793
HM vs DHA
0.000
|
HM
56
14.583
0.287
14.729
HM vs DHA + ARA
0.000
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.661
|
40 Weeks PCA
18:1
Control
37
17.894
0.453
18.636
0.256
|
DHA
32
17.766
0.429
18.492
|
DHA + ARA
38
17.850
0.289
18.227
|
HM
56
18.662
0.305
18.727
|
48 Weeks PCA
18:2
Control
37
23.469
0.518
23.552
0.000
Control vs DHA
0.840
|
DHA
32
23.538
0.516
23.717
Control vs DHA + ARA
0.527
|
DHA + ARA
38
23.738
0.422
23.839
HM vs DHA
0.000
|
HM
56
18.650
0.344
18.482
HM vs DHA + ARA
0.000
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.685
|
48 Weeks PCA
18:3n6
Control
37
0.071
0.008
0.061
0.002
Control vs DHA
0.950
|
DHA
32
0.069
0.005
0.067
Control vs DHA + ARA
0.774
|
DHA + ARA
38
0.069
0.006
0.062
HM vs DHA
0.004
|
HM
56
0.042
0.004
0.039
HM vs DHA + ARA
0.001
|
Control vs HM
0.003
|
DHA vs DHA + ARA
0.831
|
48 Weeks PCA
20:0
Control
37
0.348
0.075
0.197
0.785
|
DHA
32
0.339
0.061
0.206
|
DHA + ARA
38
0.304
0.061
0.172
|
HM
56
0.409
0.044
0.215
|
48 Weeks PCA
18:3n3
Control
37
0.222
0.019
0.182
0.001
Control vs DHA
0.812
|
DHA
32
0.211
0.015
0.182
Control vs DHA + ARA
0.918
|
DHA + ARA
38
0.203
0.010
0.190
HM vs DHA
0.001
|
HM
56
0.182
0.022
0.120
HM vs DHA + ARA
0.002
|
Control vs HM
0.001
|
DHA vs DHA + ARA
0.737
|
48 Weeks PCA
20:1
Control
37
0.418
0.019
0.420
0.000
Control vs DHA
0.579
|
DHA
32
0.406
0.025
0.435
Control vs DHA + ARA
0.588
|
DHA + ARA
38
0.382
0.016
0.375
HM vs DHA
0.001
|
HM
56
0.311
0.014
0.309
HM vs DHA + ARA
0.001
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.974
|
48 Weeks PCA
18:4
Control
37
0.018
0.005
0.000
0.010
Control vs DHA
0.822
|
DHA
32
0.016
0.004
0.000
Control vs DHA + ARA
0.161
|
DHA + ARA
38
0.007
0.002
0.000
HM vs DHA
0.039
|
HM
56
0.024
0.004
0.015
HM vs DHA + ARA
0.001
|
Control vs HM
0.054
|
DHA vs DHA + ARA
0.262
|
48 Weeks PCA
20:2n6
Control
37
0.543
0.023
0.537
0.629
|
DHA
32
0.557
0.032
0.543
|
DHA + ARA
38
0.636
0.053
0.550
|
HM
56
0.560
0.014
0.531
|
48 Weeks PCA
20:3n6
Control
37
1.709
0.086
1.741
0.000
Control vs DHA
0.610
|
DHA
32
1.702
0.073
1.684
Control vs DHA + ARA
0.735
|
DHA + ARA
38
1.844
0.090
1.717
HM vs DHA
0.000
|
HM
56
2.265
0.086
2.166
HM vs DHA + ARA
0.000
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.405
|
48 Weeks PCA
20:4n6
Control
37
4.738
0.255
4.736
0.000
Control vs DHA
0.508
|
DHA
32
4.475
0.196
4.499
Control vs DHA + ARA
0.805
|
DHA + ARA
38
4.550
0.185
4.746
HM vs DHA
0.000
|
HM
56
7.408
0.250
7.666
HM vs DHA + ARA
0.000
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.672
|
48 Weeks PCA
22:1
Control
37
0.166
0.036
0.131
0.664
|
DHA
32
0.116
0.014
0.118
|
DHA + ARA
38
0.131
0.024
0.105
|
HM
56
0.160
0.030
0.104
|
48 Weeks PCA
20:5n3
Control
37
0.102
0.015
0.077
0.000
Control vs DHA
0.663
|
DHA
32
0.084
0.006
0.083
Control vs DHA + ARA
0.086
|
DHA + ARA
38
0.099
0.009
0.078
HM vs DHA
0.000
|
HM
56
0.138
0.009
0.123
HM vs DHA + ARA
0.000
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.239
|
48 Weeks PCA
22:4n6
Control
37
0.426
0.059
0.373
0.244
|
DHA
32
0.382
0.029
0.417
|
DHA + ARA
38
0.440
0.054
0.384
|
HM
56
0.406
0.022
0.377
|
48 Weeks PCA
24:1
Control
37
0.247
0.070
0.112
0.000
Control vs DHA
0.337
|
DHA
32
0.210
0.062
0.116
Control vs DHA + ARA
0.247
|
DHA + ARA
38
0.179
0.055
0.108
HM vs DHA
0.000
|
HM
56
0.115
0.020
0.079
HM vs DHA + ARA
0.000
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.878
|
48 Weeks PCA
22:5n6
Control
37
0.210
0.016
0.212
0.000
Control vs DHA
0.505
|
DHA
32
0.189
0.012
0.186
Control vs DHA + ARA
0.647
|
DHA + ARA
38
0.231
0.022
0.198
HM vs DHA
0.000
|
HM
56
0.264
0.016
0.265
HM vs DHA + ARA
0.001
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.270
|
48 Weeks PCA
22:4n3
Control
37
0.000
0.000
0.000
1.000
|
DHA
32
0.000
0.000
0.000
|
DHA + ARA
38
0.000
0.000
0.000
|
HM
56
0.000
0.000
0.000
|
48 Weeks PCA
22:5n3
Control
37
0.286
0.029
0.260
0.000
Control vs DHA
0.598
|
DHA
32
0.253
0.017
0.251
Control vs DHA + ARA
0.759
|
DHA + ARA
38
0.268
0.026
0.256
HM vs DHA
0.000
|
HM
56
0.339
0.018
0.314
HM vs DHA + ARA
0.000
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.817
|
48 Weeks PCA
22:6n3
Control
37
0.595
0.047
0.569
0.000
Control vs DHA
0.111
|
DHA
32
0.685
0.048
0.676
Control vs DHA + ARA
0.052
|
DHA + ARA
38
0.662
0.043
0.663
HM vs DHA
0.000
|
HM
56
1.475
0.081
1.333
HM vs DHA + ARA
0.000
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.776
|
|
[0164]
12
TABLE 10
|
|
|
Red Blood Cell Phosphatidylethanolamine Fatty Acids
|
Fatty
Arithmetic
Standard
Regimen
Pairwise
Pairwise
|
Time
Acid
Regimen
n
Mean
Error
Median
p-value
Comparison
p-value
|
|
Study Form Initiation
12:0
Control
52
0.069
0.015
0.022
0.546
|
DHA
57
0.075
0.013
0.033
|
DHA + ARA
61
0.063
0.010
0.039
|
Study Form Initiation
14:0
Control
52
0.307
0.038
0.220
0.792
|
DHA
57
0.278
0.025
0.206
|
DHA + ARA
61
0.277
0.021
0.246
|
Study Form Initiation
14:1
Control
52
0.080
0.015
0.032
0.181
|
DHA
57
0.061
0.012
0.028
|
DHA + ARA
61
0.062
0.009
0.050
|
Study Form Initiation
16:0
Control
52
20.021
0.736
17.945
0.967
|
DHA
57
19.847
0.622
19.295
|
DHA + ARA
61
19.796
0.451
19.035
|
Study Form Initiation
16:1
Control
52
0.731
0.035
0.698
0.337
|
DHA
57
0.769
0.034
0.746
|
DHA + ARA
61
0.836
0.035
0.837
|
Study Form Initiation
18:0
Control
52
8.857
0.329
8.469
0.142
|
DHA
57
8.434
0.227
8.308
|
DHA + ARA
61
8.201
0.215
7.904
|
Study Form Initiation
18:1
Control
52
16.450
0.301
16.698
0.412
|
DHA
57
16.208
0.326
16.308
|
DHA + ARA
61
16.415
0.375
16.001
|
Study Form Initiation
18:2
Control
52
6.615
0.253
6.682
0.773
|
DHA
57
6.336
0.280
6.346
|
DHA + ARA
61
6.175
0.294
5.682
|
Study Form Initiation
18:3n6
Control
52
0.165
0.018
0.145
0.040
Control vs DHA
0.373
|
DHA
57
0.190
0.019
0.152
Control vs DHA + ARA
0.013
|
DHA + ARA
61
0.192
0.016
0.169
DHA vs DHA + ARA
0.101
|
Study Form Initiation
20:0
Control
52
0.372
0.043
0.291
0.51
|
DHA
57
0.314
0.030
0.244
|
DHA + ARA
61
0.259
0.024
0.186
|
Study Form Initiation
18:3n3
Control
52
0.305
0.023
0.261
0.641
|
DHA
57
0.269
0.018
0.249
|
DHA + ARA
61
0.257
0.016
0.225
|
Study Form Initiation
20:1
Control
52
0.573
0.036
0.517
0.395
|
DHA
57
0.615
0.034
0.555
|
DHA + ARA
61
0.571
0.027
0.544
|
Study Form Initiation
18:4
Control
52
0.025
0.005
0.000
0.371
|
DHA
57
0.031
0.004
0.025
|
DHA + ARA
61
0.030
0.007
0.021
|
Study Form Initiation
20:2n6
Control
52
0.479
0.023
0.480
0.706
|
DHA
57
0.463
0.024
0.437
|
DHA + ARA
61
0.443
0.028
0.427
|
Study Form Initiation
20:3n6
Control
52
1.843
0.072
1.829
0.099
|
DHA
57
1.965
0.077
1.820
|
DHA + ARA
61
1.973
0.064
1.911
|
Study Form Initiation
20:4n6
Control
52
25.817
0.618
26.820
0.353
|
DHA
57
26.475
0.611
27.376
|
DHA + ARA
61
26.747
0.645
27.708
|
Study Form Initiation
22:1
Control
52
0.150
0.017
0.138
0.572
|
DHA
57
0.167
0.015
0.151
|
DHA + ARA
61
0.168
0.017
0.141
|
Study Form Initiation
20:5n3
Control
52
0.378
0.024
0.357
0.997
|
DHA
57
0.384
0.024
0.370
|
DHA + ARA
61
0.366
0.022
0.335
|
Study Form Initiation
22:4n6
Control
52
7.290
0.182
7.402
0.875
|
DHA
57
7.431
0.186
7.836
|
DHA + ARA
61
7.456
0.167
7.270
|
Study Form Initiation
24:1
Control
52
0.100
0.028
0.041
0.068
|
DHA
57
0.059
0.009
0.031
|
DHA + ARA
61
0.072
0.010
0.047
|
Study Form Initiation
22:5n6
Control
52
1.757
0.083
1.782
0.555
|
DHA
57
1.809
0.070
1.857
|
DHA + ARA
61
1.851
0.075
1.775
|
Study Form Initiation
22:4n3
Control
52
0.001
0.001
0.000
0.257
|
DHA
57
0.001
0.001
0.000
|
DHA + ARA
61
0.005
0.002
0.000
|
Study Form Initiation
22:5n3
Control
52
1.496
0.109
1.308
0.195
|
DHA
57
1.375
0.109
1.041
|
DHA + ARA
61
1.380
0.097
1.041
|
Study Form Initiation
22:6n3
Control
52
6.119
0.200
6.381
0.375
|
DHA
57
6.444
0.185
6.468
|
DHA + ARA
61
6.407
0.220
6.579
|
Study Form Termination
12:0
Control
53
0.093
0.018
0.033
0.630
|
DHA
55
0.093
0.019
0.036
|
DHA + ARA
58
0.067
0.012
0.035
|
Study Form Termination
14:0
Control
53
0.360
0.031
0.279
0.782
|
DHA
55
0.380
0.039
0.265
|
DHA + ARA
58
0.348
0.030
0.256
|
Study Form Termination
14:1
Control
53
0.086
0.020
0.041
0.592
|
DHA
55
0.066
0.013
0.000
|
DHA + ARA
58
0.066
0.011
0.043
|
Study Form Termination
16:0
Control
53
19.326
0.673
17.617
0.560
|
DHA
55
19.062
0.614
17.556
|
DHA + ARA
58
18.357
0.467
17.568
|
Study Form Termination
16:1
Control
53
0.511
0.034
0.476
0.604
|
DHA
55
0.579
0.045
0.509
|
DHA + ARA
58
0.618
0.049
0.555
|
Study Form Termination
18:0
Control
53
9.614
0.266
9.406
0.024
Control vs DHA
0.130
|
DHA
55
9.173
0.208
8.818
Control vs DHA + ARA
0.006
|
DHA + ARA
58
8.961
0.242
8.697
DHA vs DHA + ARA
0.219
|
Study Form Termination
18:1
Control
53
14.763
0.437
14.695
0.333
|
DHA
55
15.177
0.299
14.927
|
DHA + ARA
58
14.814
0.330
14.499
|
Study Form Termination
18:2
Control
53
9.405
0.192
9.359
0.000
Control vs DHA
0.908
|
DHA
55
9.180
0.207
9.188
Control vs DHA + ARA
0.000
|
DHA + ARA
58
7.756
0.141
7.586
DHA vs DHA + ARA
0.000
|
Study Form Termination
18:3n6
Control
53
0.169
0.012
0.163
0.160
|
DHA
55
0.187
0.017
0.157
|
DHA + ARA
58
0.198
0.018
0.161
|
Study Form Termination
20:0
Control
53
0.404
0.044
0.278
0.146
|
DHA
55
0.336
0.037
0.208
|
DHA + ARA
50
0.288
0.029
0.208
|
Study Form Termination
18:3n3
Control
53
0.382
0.017
0.364
0.134
|
DHA
55
0.368
0.016
0.354
|
DHA + ARA
58
0.329
0.015
0.305
|
Study Form Termination
20:1
Control
53
0.553
0.029
0.526
0.164
|
DHA
55
0.579
0.028
0.537
|
DHA + ARA
58
0.507
0.025
0.483
|
Study Form Termination
18:4
Control
53
0.042
0.010
0.018
0.108
|
DHA
55
0.026
0.005
0.019
|
DHA + ARA
58
0.022
0.004
0.000
|
Study Form Termination
20:2n6
Control
53
0.754
0.029
0.765
0.068
|
DHA
55
0.774
0.030
0.750
|
DHA + ARA
58
0.654
0.026
0.663
|
Study Form Termination
20:3n6
Control
53
2.253
0.111
2.073
0.203
|
DHA
55
2.295
0.094
2.206
|
DHA + ARA
58
2.066
0.073
1.992
|
Study Form Termination
20:4n6
Control
53
24.279
0.527
25.132
0.000
Control vs DHA
0.119
|
DHA
55
23.464
0.520
24.038
Control vs DHA + ARA
0.000
|
DHA + ARA
58
26.760
0.437
27.372
DHA vs DHA + ARA
0.000
|
Study Form Termination
22:1
Control
53
0.149
0.019
0.122
0.229
|
DHA
55
0.176
0.016
0.169
|
DHA + ARA
58
0.146
0.012
0.130
|
Study Form Termination
20:5n3
Control
53
0.519
0.020
0.493
0.000
Control vs DHA
0.286
|
DHA
55
0.563
0.025
0.575
Control vs DHA + ARA
0.000
|
DHA + ARA
58
0.411
0.015
0.415
DHA vs DHA + ARA
0.000
|
Study Form termination
22:4n6
Control
53
7.309
0.208
7.656
0.007
Control vs DHA
0.025
|
DHA
55
7.135
0.154
6.885
Control vs DHA + ARA
0.461
|
DHA + ARA
58
7.592
0.155
7.635
DHA vs DHA + ARA
0.002
|
Study Form Termination
24:1
Control
53
0.092
0.023
0.038
0.294
|
DHA
55
0.056
0.009
0.042
|
DHA + ARA
58
0.062
0.008
0.041
|
Study Form Termination
22:5n6
Control
53
1.444
0.064
1.423
0.010
Control vs DHA
0.003
|
DHA
55
1.231
0.034
1.213
Control vs DHA + ARA
0.255
|
DHA + ARA
58
1.347
0.040
1.330
DHA vs DHA + ARA
0.050
|
Study Form Termination
22:4n3
Control
53
0.000
0.000
0.000
0.137
|
DHA
55
0.004
0.002
0.000
|
DHA + ARA
58
0.004
0.002
0.000
|
Study Form Termination
22:5n3
Control
53
2.694
0.110
2.839
0.003
Control vs DHA
0.040
|
DHA
55
2.334
0.091
2.400
Control vs DHA + ARA
0.002
|
DHA + ARA
58
2.237
0.069
2.269
DHA vs DHA + ARA
0.943
|
Study Form Termination
22:6n3
Control
53
4.798
0.151
4.815
0.000
Control vs DHA
0.000
|
DHA
55
6.762
0.183
7.043
Control vs DHA + ARA
0.000
|
DHA + ARA
58
6.389
0.150
6.498
DHA vs DHA + ARA
0.027
|
48 Weeks PCA
12:0
Control
37
0.053
0.019
0.024
0.587
|
DHA
32
0.054
0.016
0.019
|
DHA + ARA
38
0.047
0.014
0.018
|
HM
56
0.045
0.011
0.023
|
48 Weeks PCA
14:0
Control
37
0.243
0.030
0.169
0.598
|
DHA
32
0.251
0.041
0.162
|
DHA + ARA
38
0.235
0.025
0.188
|
HM
56
0.230
0.016
0.210
|
48 Weeks PCA
14:1
Control
37
0.080
0.017
0.037
0.092
|
DHA
32
0.055
0.017
0.000
|
DHA + ARA
38
0.078
0.019
0.044
|
HM
56
0.053
0.011
0.021
|
48 Weeks PCA
16:0
Control
37
17.319
0.595
16.314
0.177
|
DHA
32
17.101
0.729
15.692
|
DHA + ARA
38
17.225
0.538
16.997
|
HM
56
18.138
0.395
17.607
|
48 Weeks PCA
16:1
Control
37
0.440
0.050
0.349
0.000
Control vs DHA
0.601
|
DHA
32
0.390
0.035
0.336
Control vs DHA + ARA
0.524
|
DHA + ARA
38
0.390
0.022
0.376
HM vs DHA
0.000
|
HM
56
0.596
0.027
0.562
HM vs DHA + ARA
0.000
|
Control vs HM
0.001
|
DHA vs DHA + ARA
0.928
|
48 Weeks PCA
18:0
Control
37
7.935
0.327
7.174
0.000
Control vs DHA
0.347
|
DHA
32
7.962
0.293
7.552
Control vs DHA + ARA
0.483
|
DHA + ARA
38
7.443
0.270
7.173
HM vs DHA
0.020
|
HM
56
8.754
0.230
8.409
HM vs DHA + ARA
0.000
|
Control vs HM
0.001
|
DHA vs DHA + ARA
0.108
|
48 Weeks PCA
18:1
Control
37
19.438
0.368
19.410
0.038
Control vs DHA
0.401
|
DHA
32
19.066
0.421
19.534
Control vs DHA + ARA
0.423
|
DHA + ARA
38
19.302
0.332
19.433
HM vs DHA
0.067
|
HM
56
18.469
0.278
18.141
HM vs DHA + ARA
0.118
|
Control vs HM
0.005
|
DHA vs DHA + ARA
0.758
|
48 Weeks PCA
18:2
Control
37
9.328
0.261
9.267
0.000
Control vs DHA
0.024
|
DHA
32
8.867
0.210
8.696
Control vs DHA + ARA
0.187
|
DHA + ARA
38
9.257
0.216
8.840
HM vs DHA
0.000
|
HM
56
6.291
0.193
6.027
HM vs DHA + ARA
0.000
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.318
|
48 Weeks PCA
18:3n6
Control
37
0.198
0.020
0.182
0.050
Control vs DHA
0.879
|
DHA
32
0.219
0.031
0.171
Control vs DHA + ARA
0.590
|
DHA + ARA
38
0.188
0.021
0.158
HM vs DHA
0.029
|
HM
56
0.129
0.012
0.112
HM vs DHA + ARA
0.061
|
Control vs HM
0.014
|
DHA vs DHA + ARA
0.714
|
48 Weeks PCA
20:0
Control
37
0.263
0.058
0.146
0.728
|
DHA
32
0.262
0.042
0.145
|
DHA + ARA
38
0.212
0.037
0.125
|
HM
56
0.295
0.031
0.240
|
48 Weeks PCA
18:3n3
Control
37
0.291
0.025
0.225
0.001
Control vs DHA
0.559
|
DHA
32
0.270
0.017
0.262
Control vs DHA + ARA
0.848
|
DHA + ARA
38
0.265
0.015
0.245
HM vs DHA
0.008
|
HM
56
0.226
0.020
0.169
HM vs DHA + ARA
0.002
|
Control vs HM
0.001
|
DHA vs DHA + ARA
0.689
|
48 Weeks PCA
20:1
Control
37
0.715
0.031
0.648
0.000
Control vs DHA
0.339
|
DHA
32
0.772
0.032
0.782
Control vs DHA + ARA
0.512
|
DHA + ARA
38
0.936
0.188
0.138
HM vs DHA
0.000
|
HM
56
0.533
0.024
0.492
HM vs DHA + ARA
0.000
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.115
|
48 Weeks PCA
18:4
Control
37
0.017
0.005
0.003
0.057
|
DHA
32
0.017
0.005
0.000
|
DHA + ARA
38
0.023
0.006
0.000
|
HM
56
0.027
0.004
0.019
|
48 Weeks PCA
20:2n6
Control
37
0.672
0.035
0.698
0.000
Control vs DHA
0.543
|
DHA
32
0.668
0.026
0.684
Control vs DHA + ARA
0.532
|
DHA + ARA
38
0.715
0.032
0.689
HM vs DHA
0.000
|
HM
56
0.444
0.016
0.412
HM vs DHA + ARA
0.000
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.995
|
48 Weeks PCA
20:3n6
Control
37
2.138
0.099
1.999
0.012
Control vs DHA
0.896
|
DHA
32
2.165
0.100
2.045
Control vs DHA + ARA
0.935
|
DHA + ARA
38
2.172
0.114
2.132
HM vs DHA
0.015
|
HM
56
1.715
0.053
1.637
HM vs DHA + ARA
0.006
|
Control vs HM
0.007
|
DHA vs DHA + ARA
0.835
|
48 Weeks PCA
20:4n6
Control
37
24.508
0.536
24.774
0.950
|
DHA
32
24.428
0.491
25.206
|
DHA + ARA
38
24.788
0.429
25.122
|
HM
56
24.625
0.384
25.189
|
48 Weeks PCA
22:1
Control
37
0.168
0.016
0.172
0.121
|
DHA
32
0.189
0.022
0.188
|
DHA + ARA
38
0.154
0.022
0.133
|
HM
56
0.148
0.013
0.134
|
48 Weeks PCA
20:5n3
Control
37
0.382
0.026
0.368
0.497
|
DHA
32
0.369
0.015
0.377
|
DHA + ARA
38
0.347
0.011
0.347
|
HM
56
0.384
0.016
0.360
|
48 Weeks PCA
22:4n6
Control
37
8.580
0.267
8.761
0.001
Control vs DHA
0.612
|
DHA
32
8.791
0.250
9.132
Control vs DHA + ARA
0.416
|
DHA + ARA
38
8.576
0.188
8.472
HM vs DHA
0.000
|
HM
56
7.727
0.203
7.618
HM vs DHA + ARA
0.013
|
Control vs HM
0.001
|
DHA vs DHA + ARA
0.199
|
48 Weeks PCA
24:1
Control
37
0.067
0.016
0.035
0.943
|
DHA
32
0.049
0.009
0.034
|
DHA + ARA
38
0.046
0.008
0.036
|
HM
56
0.062
0.016
0.027
|
48 Weeks PCA
22:5n6
Control
37
1.401
0.066
1.411
0.000
Control vs DHA
0.977
|
DHA
32
1.353
0.057
1.414
Control vs DHA + ARA
0.997
|
DHA + ARA
38
1.364
0.054
1.359
HM vs DHA
0.000
|
HM
56
1.883
0.056
1.889
HM vs DHA + ARA
0.000
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.975
|
48 Weeks PCA
22:4n3
Control
37
0.000
0.000
0.000
1.000
|
DHA
32
0.000
0.000
0.000
|
DHA + ARA
38
0.000
0.000
0.000
|
HM
56
0.001
0.001
0.000
|
48 Weeks PCA
22:5n3
Control
37
2.567
0.092
2.681
0.000
Control vs DHA
0.884
|
DHA
32
2.561
0.086
2.630
Control vs DHA + ARA
0.148
|
DHA + ARA
38
2.436
0.066
2.443
HM vs DHA
0.000
|
HM
56
1.942
0.065
1.978
HM vs DHA + ARA
0.000
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.213
|
48 Weeks PCA
22:6n3
Control
37
3.196
0.159
3.013
0.000
Control vs DHA
0.000
|
DHA
32
4.143
0.177
4.079
Control vs DHA + ARA
0.000
|
DHA + ARA
38
3.801
0.134
3.721
HM vs DHA
0.000
|
HM
56
7.283
0.201
7.341
HM vs DHA + ARA
0.000
|
Control vs HM
0.000
|
DHA vs DHA + ARA
0.281
|
|
[0165]
13
TABLE 11
|
|
|
Preterm Infant Complications
|
Regimen
|
DHA +
|
Control
DHA
ARA
p-value*
|
|
Retinopathy of
|
Prematurity Test Results
|
Absent
34 (76%)
44 (76%)
41 (79%)
0.91
|
I
8 (18%)
11 (19%)
6 (12%)
|
II
2 (4%)
2 (3%)
4 (8%)
|
III
1 (2%)
1 (2%)
|
Present, but not
|
graded
1 (2%)
|
Ultrasound Examination
|
for Intraventricular
|
Hemorrhage
|
None
47 (81%)
52 (84%)
49 (80%)
0.78
|
Stage 1
6 (10%)
9 (15%)
7 (11%)
|
Stage 2
3 (5%)
2 (3%)
|
Stage 3
1 (2%)
1 (2%)
|
Stage 4
1 (2%)
2 (3%)
|
Questionable
1 (2%)
|
Posthemorrhagic
|
Hydrocephalus
|
developed?
|
No
61 (98%)
65 (98%)
64 (97%)
1.00
|
Yes
1 (2%)
1 (2%)
2 (3%)
|
|
*The statistical test was based on a dichotomous response: present or absent.
|
[0166]
14
TABLE 12
|
|
|
Serious Adverse Events Reported During Study Formula Phase
|
Regimen
|
DHA +
|
Event
Control
DHA
ARA
p-value
|
|
Any Event
4 (6%)
3 (5%)
4 (6%)
0.93
|
Other Respiratory Conditions
2 (3%)
0
0
0.10
|
of Fetus and Newborn
|
Other Infection Specific to
1 (2%)
0
0
0.32
|
the Perinatal Period
|
Intraventricular Hemorrhage
0
0
1 (2%)
1.00
|
Other Specified Perinatal
0
1 (2%)
0
1.00
|
Disorders of Digestive System
|
Convulsions in Newborn
1 (2%)
0
0
0.32
|
Feeding Problems in Newborn
0
1 (2%)
1 (2%)
1.00
|
Hernia
0
0
1 (2%)
1.00
|
Other
0
1 (2%)
1 (2%)
1.00
|
|
[0167]
15
TABLE 13
|
|
|
Serious Adverse Events Reported During the Term Formula Phase
|
Regimen
|
Event
Control
DHA
DHA + ARA
HM
p-value
|
|
Any Event
7 (13%)
9 (15%)
9 (15%)
1 (1%)
0.002
|
C vs D
0.79
|
C vs D + A
0.79
|
D vs D + A
1.00
|
C vs HM
0.006
|
D vs HM
0.001
|
D + A vs HM
0.001
|
Infectious Colitis,
0
0
1 (2%)
0
0.67
|
Enteritis, and
|
Gastroenteritis
|
Croup
0
0
1 (2%)
0
0.67
|
Bronchopneumonia,
2 (4%)
3 (5%)
6 (10%)
0
0.013
|
Organism Unspecified
C vs D
1.00
|
C vs D + A
0.27
|
D vs D + A
0.49
|
C vs HM
0.15
|
D vs HM
0.064
|
D + A vs HM
0.004
|
Asthma, Unspecified
1 (2%)
0
0
0
0.21
|
Esophageal Reflux
0
1 (2%)
2 (3%)
0
0.23
|
Dyspepsia and Other
0
0
0
1 (1%)
1.0
|
Stomach Function
|
Disorder
|
Other Respiratory
1 (2%)
1 (2%)
3 (5%)
0
0.11
|
Conditions of Fetus
|
and Newborn
|
ConvulsiOns
1 (2%)
0
0
0
0.21
|
Sudden Infant Death
1 (2%)
1 (2%)
0
0
0.34
|
Syndrome
|
Eernia
2 (4%)
2 (3%)
0
0
0.11
|
Other
0
3 (5%)
2 (3%)
0
0.063
|
|
[0168]
16
APPENDIX 1
|
|
|
Listing of Weights Included in the Statistical Analyses
|
Growth
|
Gender
Regimen
Subject
Variable
Wgt1
Wgt2
Wgt3
Wgt4
Wgt5
Wgt6
Wgt7
Wgt8
Wgt9
Rate g/day
Wgt_40
Wgt_48
Wgt_57
|
|
Male
Control
9698-0301
Weight (g)
1120
1240
1360
1590
1870
27.7
|
Age (weeks pca)
30.3
31.3
32.1
33.1
34.1
|
Male
Control
9698-0304
Weight (g)
1450
1630
1940
2180
36.1
3731
5752
6816
|
Age (weeks pca)
32.6
33.4
34.7
35.4
40.3
48.3
56.6
|
Male
Control
9699-0302
Weight (g) 958.0
1108
1251
1378
1659
23.9
3064
4993
6553
|
Age (weeks pca)
30.7
31.7
32.7
33.7
34.7
39.9
48.0
57.9
|
Male
Control
9699-0306
Weight (g)
1185
1261
1437
1647
1933
26.9
3575
4936
6014
|
Age (weeks pca)
31.0
32.0
33.0
34.0
35.0
40.3
48.3
57.1
|
Male
Control
9699-0308
Weight (g)
1600
1840
2752
43.3
3688
5504
6922
|
Age (weeks pca)
34.4
35.4
38.3
40.3
48.3
57.3
|
Male
Control
9700-0301
Weight (g)
1810
1855
2075
2330
2595
3120
36.2
3745
5080
6610
|
Age (weeks pca)
32.1
32.6
33.4
34.4
35.4
37.4
40.1
47.6
56.7
|
Male
Control
9701-0303
Weight (g)
1181
1298
1494
1785
2012
31.5
3070
3895
4965
|
Age (weeks pca)
32.4
33.4
34.4
35.4
36.3
41.6
48.6
57.6
|
Male
Control
9701-0304
Weight (g)
1412
1566
1851
2117
2318
34.1
3070
5445
7135
|
Age (weeks pca)
31.9
32.9
33.7
34.7
35.9
39.9
48.3
56.9
|
Male
Control
9702-0302
Weight (g)
1480
1775
2045
2240
2340
2570
33.8
3590
4840
6110
|
Age (weeks pca)
31.0
32.1
33.0
34.0
34.6
35.6
40.1
48.6
58.4
|
Male
Control
9703-0302
Weight (g)
1785
2040
2375
2685
2955
41.7
3620
5850
7470
|
Age (weeks pca)
33.3
34.6
35.6
36.4
37.4
39.7
48.6
57.3
|
Male
Control
9703-0304
Weight (g)
1475
1705
1920
2190
2425
34.2
3170
5240
6970
|
Age (weeks pca)
31.7
33.0
34.0
34.9
35.7
40.1
47.7
57.1
|
Male
Control
9703-0308
Weight (g)
1140
1230
1445
1665
1945
28.9
2520
4010
5030
|
Age (weeks pca)
31.7
32.6
33.7
34.7
35.7
39.7
48.4
56.9
|
Male
Control
9704-0303
Weight (g)
975.0
1205
1270
1450
1665
1760
2045
24.4
2150
3700
4950
|
Age (weeks pca)
32.3
33.4
34.4
35.4
36.3
37.3
38.3
39.3
48.3
57.4
|
Male
Control
9704-0305
Weight (g)
1315
1475
1640
1860
23.7
|
Age (weeks pca)
30.9
32.0
33.0
34.1
|
Male
Control
9705-0302
Weight (g)
1280
1389
1588
1786
2240
30.9
2540
4936
5646
|
Age (weeks pca)
33.0
34.0
35.0
36.0
37.4
39.6
47.4
56.4
|
Male
Control
9705-0304
Weight (g)
1270
1280
1570
1810
25.3
3291
5816
7490
|
Age (weeks pca)
31.3
32.3
33.3
34.6
39.7
47.7
56.7
|
Male
Control
9706-0302
Weight (g)
1645
1865
2130
2435
37.1
2800
4660
6170
|
Age (weeks pca)
35.7
36.6
37.7
38.7
40.1
48.7
56.7
|
Male
Control
9706-0303
Weight (g)
1875
1984
2135
2185
2465
22.2
3050
4550
6675
|
Age (weeks pca)
33.7
34.7
35.6
36.4
37.3
41.0
48.6
56.9
|
Male
Control
9706-0308
Weight (g)
1655
1734
2005
2495
46.9
3835
5155
6090
|
Age (weeks pca)
32.9
33.1
34.0
35.4
40.6
48.0
56.3
|
Male
Control
9707-0302
Weight (g)
1544
1820
2215
2450
2460
32.8
2930
3795
5185
|
Age (weeks pca)
31.6
32.9
34.4
35.4
35.7
39.7
47.7
57.1
|
Male
Control
9707-0303
Weight (g)
1415
1600
1850
2195
2310
32.7
2530
4235
6530
|
Age (weeks pca)
33.1
34.1
35.1
36.6
37.1
39.7
47.7
57.1
|
Male
Control
9707-0309
Weight (g)
1046
1442
1644
1910
30.7
2965
4465
|
Age (weeks pca)
30.9
32.7
33.7
34.9
39.9
48.0
|
Male
Control
9708-0303
Weight (g)
1730
1960
2205
2520
37.4
3680
5470
7330
|
Age (weeks pca)
32.7
33.7
34.7
35.7
40.1
48.1
57.0
|
Male
Control
9709-0302
Weight (g)
1090
1440
1660
1910
2040
30.8
3845
5700
6775
|
Age (weeks pca)
29.9
31.7
32.7
33.7
34.3
39.9
48.0
56.7
|
Male
Control
9712-0301*
Weight (g)
1245
1221
1245
1291
1294
1330
1369
1402
1433
26.1
|
Age (weeks pca)
31.6
31.7
31.9
32.0
32.1
32.3
32.4
32.6
32.7
|
Male
Control
9712-0302
Weight (g)
1292
1345
1456
1670
1835
1985
21.0
2160
3300
3980
|
Age (weeks pca)
33.1
34.1
35.1
36.1
37.1
38.1
40.1
47.7
57.3
|
Male
Control
9743-0301
Weight (g)
1520
1570
1670
1720
10.0
2260
4535
|
Age (weeks pca)
34.1
35.0
36.0
37.1
41.0
50.0
|
Male
Control
9746-0301
Weight (g)
2065
2465
2760
3085
3085
48.9
3085
4795
6695
|
Age (weeks pca)
37.6
38.9
39.7
40.6
40.6
40.6
47.6
57.6
|
Male
DHA
9698-0302
Weight (g)
1640
1860
3170
47.5
3170
5206
7036
|
Age (weeks pca)
35.1
36.1
39.9
39.9
47.9
57.1
|
Male
DHA
9698-0306
Weight (g)
1620
1830
2090
2575
28.3
2575
4334
6022
|
Age (weeks pca)
35.1
36.3
37.3
40.0
40.0
48.0
57.0
|
Male
DHA
9699-0301
Weight (g)
1018
1207
1360
1617
27.9
3121
5192
6752
|
Age (weeks pca)
31.3
32.3
33.3
34.3
39.9
48.0
57.9
|
Male
DHA
9699-0303
Weight (g)
1258
1435
1631
1882
2724
48.3
2724
4341
5674
|
Age (weeks pca)
32.4
33.4
34.4
35.4
36.4
40.1
48.1
57.0
|
Male
DHA
9699-0307
Weight (g)
1182
1358
1484
1666
22.5
1986
3206
4511
|
Age (weeks pca)
34.7
35.7
36.7
37.7
39.6
47.4
56.7
|
Male
DHA
9700-0303
Weight (g)
1830
1980
2450
3045
45.4
3585
5420
7035
|
Age (weeks pca)
33.9
34.4
35.9
37.7
39.6
47.4
56.7
|
Male
DHA
9701-0301
Weight (g)
1098
1234
1365
1689
1902
2019
2104
2276
2288
20.4
2805
3405
4660
|
Age (weeks pca)
29.6
30.6
31.6
33.4
34.6
35.6
36.4
37.4
38.6
40.4
47.6
57.0
|
Male
DHA
9701-0305
Weight (g)
1621
1829
1880
2253
2582
34.7
3660
|
Age (weeks pca)
31.7
33.1
33.7
34.7
35.7
39.7
|
Male
DHA
9703-0303
Weight (g)
1775
2030
2285
2595
2780
38.2
3080
3940
5260
|
Age (weeks pca)
33.3
34.1
35.1
36.0
37.1
39.9
48.0
56.9
|
Male
DHA
9703-0306
weight (g)
1725
1870
2180
41.7
|
Age (weeks pca)
33.4
34.0
35.0
|
Male
DHA
9703-0307
Weight (g)
1525
1725
2020
2390
37.6
3120
4410
5600
|
Age (weeks pca)
32.7
33.7
34.9
36.0
40.7
47.9
56.9
|
Male
DHA
9704-0304
Weight (g)
1380
1570
1730
1960
2140
29.3
2880
3900
4300
|
Age (weeks pca)
32.1
33.1
34.1
35.0
35.9
40.3
48.3
57.3
|
Male
DHA
9704-0306
Weight (g)
1320
1370
1550
1760
2020
2170
25.6
3750
4800
|
Age (weeks pca)
30.7
31.7
32.7
33.7
34.7
35.9
48.0
57.0
|
Male
DHA
9705-0303
Weight (g)
1380
1446
1616
1843
2330
30.8
2370
4170
5787
|
Age (weeks pca)
33.0
34.0
35.0
36.0
37.4
39.6
47.4
56.4
|
Male
DHA
9705-0305
Weight (g)
1490
1770
1980
2240
36.7
3291
|
Age (weeks pca)
31.1
32.1
33.1
34.0
39.6
|
Male
DHA
9706-0304
Weight (g)
1490
1655
1915
2260
36.8
3335
5265
6900
|
Age (weeks pca)
33.0
33.7
34.7
36.0
40.0
48.1
57.3
|
Male
DHA
9706-0306
Weight (g)
1604
1908
2160
42.8
3310
4205
5600
|
Age (weeks pca)
34.4
35.4
36.3
41.4
47.6
56.9
|
Male
DHA
9707-0001
Weight (g)
1305
1429
17.7
|
Age (weeks pca)
31.0
32.0
|
Male
DHA
9707-0304
Weight (g)
1555
1740
1990
2400
2570
36.9
3280
5115
6755
|
Age (weeks pca)
32.0
33.0
34.0
35.4
36.0
39.9
48.0
57.6
|
Male
DHA
9707-0306
Weight (g)
1728
2040
2260
3050
3050
43.2
3050
5100
7150
|
Age (weeks pca)
36.1
37.3
38.1
40.6
40.6
40.6
48.6
57.6
|
Male
DHA
9707-0307*
Weight (g)
1649
1675
1699
1732
1778
1811
1858
1882
1938
39.6
|
Age (weeks pca)
32.4
32.6
32.7
32.9
33.0
33.1
33.3
33.4
33.6
|
Male
DHA
9707-1308
Weight (g)
1780
2045
3004
3004
36.7
3004
4420
6090
|
Age (weeks pca)
34.4
35.7
39.3
39.3
393.
47.3
57.7
|
Male
DHA
9707-2308
Weight (g)
1651
1923
2850
2850
35.8
2850
4375
5930
|
Age (weeks pca)
34.4
35.7
39.3
39.3
39.3
47.3
57.7
|
Male
DHA
9708-0302
Weight (g)
1485
1740
2500
39.2
3873
6256
|
Age (weeks pca)
33.3
34.3
37.0
42.9
57.3
|
Male
DHA
9709-0301
Weight (g)
1490
1740
2000
2400
2800
44.4
3150
5080
6750
|
Age (weeks pca)
32.4
33.4
34.4
35.4
36.7
39.4
47.4
56.4
|
Male
DHA
9709-0304
Weight (g)
1470
1520
7.1
|
Age (weeks pca)
34.4
35.4
|
Male
DHA
9712-0304
Weight (g)
1545
1800
1985
2160
2550
30.5
3160
5200
7300
|
Age (weeks pca)
33.0
34.0
35.0
36.0
37.6
40.3
48.1
57.1
|
Male
DHA
9712-0306
Weight (g)
1240
1435
1695
1945
33.9
3040
4680
5860
|
Age (weeks pca)
31.5
32.5
33.5
34.5
39.6
48.6
57.6
|
Male
DHA
9743-0303
Weight (g)
1700
1810
2100
2300
31.1
3100
5500
|
Age (weeks pca)
32.9
33.9
34.9
35.7
40.6
48.6
|
Male
DHA
9743-0304
Weight (g)
1530
1880
2160
2375
2440
32.2
3628
5840
|
Age (weeks pca)
32.3
34.0
35.0
36.0
36.4
38.1
50.6
|
Male
DHA + ARA
9698-0305
Weight (g)
1120
1340
1550
20.9
2440
5525
6646
|
Age (weeks pca)
30.7
32.6
33.6
37.4
47.6
56.6
|
Male
DHA + ARA
9698-0308
Weight (g)
1410
1690
1870
2120
32.0
3553
6007
7937
|
Age (weeks pca)
31.1
32.4
33.3
34.3
40.3
47.6
57.3
|
Male
DHA + ARA
9699-0304
Weight (g)
1499
1689
1950
2355
29.8
2355
3404
4993
|
Age (weeks pca)
36.1
37.1
38.1
40.3
40.3
48.0
57.1
|
Male
DHA + ARA
9699-0305
Weight (g)
1056
1134
1290
1490
17.2
2610
4256
5050
|
Age (weeks pca)
32.0
33.0
34.0
35.7
40.6
48.7
57.6
|
Male
DHA + ARA
9700-0302
Weight (g)
1635
1880
2235
2570
2735
40.7
3255
5540
7380
|
Age (weeks pca)
33.9
34.7
35.9
36.9
37.9
39.7
46.7
56.7
|
Male
DHA + ARA
9701-0302
Weight (g)
1442
1686
2045
2835
48.9
3240
5055
6600
|
Age (weeks pca)
33.6
34.6
35.6
37.7
39.7
47.7
56.7
|
Male
DHA + ARA
9701-0306
Weight (g)
1587
2037
2245
2460
2756
3072
3228
41.4
3960
5200
|
Age (weeks pca)
32.3
33.4
34.4
35.3
36.3
37.3
37.7
42.3
48.4
|
Male
DHA + ARA
9701-0307
Weight (g)
1397
1710
1919
2932
42.5
3445
5930
7475
|
Age (weeks pca)
33.3
34.3
35.1
38.4
40.6
48.6
57.4
|
Male
DHA + ARA
9702-0301
Weight (g)
1670
1865
2160
2660
36.0
3780
5250
|
Age (weeks pca)
32.0
33.0
34.0
36.0
40.6
47.6
|
Male
DHA + ARA
9702-0303
Weight (g)
1650
1905
2660
40.7
3500
5160
6520
|
Age (weeks pca)
32.9
33.9
36.4
40.0
48.0
56.4
|
Male
DHA + ARA
9703-0301
Weight (g)
1255
1460
1745
2055
2415
42.3
4350
6020
6720
|
Age (weeks pca)
29.4
30.4
31.3
32.3
33.4
40.4
47.4
56.6
|
Male
DHA + ARA
9703-0305
Weight (g)
1440
1635
1830
2115
2390
2590
34.1
3170
4330
5630
|
Age (weeks pca)
32.0
33.0
34.0
35.0
36.1
36.9
40.0
48.1
58.0
|
Male
DHA + ARA
9704-0301
Weight (g)
1110
1270
1490
1740
2050
35.1
3220
5460
7050
|
Age (weeks pca)
30.6
31.6
32.4
33.4
34.4
39.9
47.7
56.7
|
Male
DHA + ARA
9704-0302
Weight (g)
1080
1230
1370
1520
1680
1840
22.2
2570
6540
8050
|
Age (weeks pca)
32.0
33.0
34.0
34.9
36.0
36.9
40.0
48.1
58.0
|
Male
DHA + ARA
9705-0301
Weight (g)
1300
1440
1620
1870
27.0
2979
4400
5873
|
Age (weeks pca)
32.7
33.7
34.7
35.7
40.1
48.1
58.0
|
Male
DHA + ARA
9705-0306
Weight (g)
1320
1490
1700
2020
2300
32.7
3631
5447
6809
|
Age (weeks pca)
31.4
32.4
33.4
34.4
35.9
39.9
47.9
56.9
|
Male
DHA + ARA
9705-0307
Weight (g)
1480
1650
1810
2240
36.4
3007
5589
6596
|
Age (weeks pca)
34.4
35.4
36.1
37.4
39.9
48.4
56.7
|
Male
DHA + ARA
9706-0305
Weight (g)
1330
1455
1660
1930
31.4
2695
4820
6225
|
Age (weeks pca)
33.9
34.4
35.4
36.6
39.9
48.1
58.1
|
Male
DHA + ARA
9706-0307
Weight (g)
1355
1585
1825
2270
40.0
3585
5955
6925
|
Age (weeks pca)
31.9
33.0
33.9
35.1
40.4
49.1
57.6
|
Male
DHA + ARA
9706-0309
Weight (9)
1620
1910
2150
40.3
3460
5255
5775
|
Age (weeks pca)
34.1
35.3
36.0
40.9
48.7
57.4
|
Male
DHA + ARA
9707-0301
Weight (g)
1553
1980
2280
2720
41.5
3395
4950
6285
|
Age (weeks pca)
32.6
34.3
35.3
36.6
40.1
47.9
56.9
|
Male
DHA + ARA
9707-0305
Weight (g)
1755
1990
2245
2505
2770
37.4
|
Age (weeks pca)
33.9
34.7
35.7
36.7
37.7
|
Male
DHA + ARA
9707-0310
Weight (g)
1620
1828
2140
3195
44.8
3585
5170
6725
|
Age (weeks pca)
32.7
33.7
34.7
37.9
39.7
47.9
56.3
|
Male
DHA + ARA
9708-0301
Weight (g)
1640
1880
2200
2420
38.0
3730
4835
6185
|
Age (weeks pca)
32.7
33.7
34.7
35.7
40.1
47.9
57.0
|
Male
DHA + ARA
9708-0304
Weight (g)
1680
2180
55.6
|
Age (weeks pca)
34.6
35.9
|
Male
DHA + ARA
9709-0303
Weight (g)
1470
1810
48.6
|
Age (weeks pca)
32.6
33.6
|
Male
DHA + ARA
9709-0305
Weight (g)
1410
1655
1900
2160
35.6
2630
4570
5520
|
Age (weeks pca)
34.4
35.4
36.4
37.4
39.7
47.7
57.1
|
Male
DHA + ARA
9712-0303
Weight (g)
1180
1210
1450
1590
20.9
2520
3500
5010
|
Age (weeks pca)
31.4
32.3
33.4
34.4
40.4
47.4
56.4
|
Male
DHA + ARA
9712-0305
Weight (g)
1325
1505
1785
2010
2300
34.1
3030
4350
5510
|
Age (weeks pca)
31.5
32.5
33.5
34.5
35.6
39.6
48.6
57.6
|
Male
DHA + ARA
9723-0301
Weight (g)
1630
1728
1961
2214
28.4
3104
5986
|
Age (weeks pca)
33.9
34.9
35.9
36.9
40.3
58.9
|
Male
HM
9698-0601
3518
5497
6582
|
40.0
48.3
56.9
|
male
HM
9698-0602
3177
5220
6355
|
40.0
48.1
57.0
|
Male
HM
9698-0603
3858
5447
6454
|
40.0
48.0
57.0
|
Male
HM
9698-0604
4355
5092
6383
|
40.0
48.0
57.0
|
Male
HM
9698-0605
3433
4979
6426
|
40.0
48.1
57.1
|
Male
HM
9699-0501
3915
6639
7773
|
40.0
48.3
57.4
|
Male
HM
9699-0502
3802
5787
7178
|
40.0
47.9
56.4
|
Male
HM
9701-0601
3487
5833
8070
|
40.0
47.9
56.4
|
Male
HM
9701-0602
3487
5833
8070
|
40.0
47.3
58.3
|
Male
HM
9701-0603
3232
4940
5855
|
40.0
47.4
56.4
|
Male
HM
9701-0604
3600
5215
6285
|
40.0
47.9
56.9
|
Male
HM
9701-0605
3402
5575
7210
|
40.0
47.6
57.6
|
Male
HM
9701-0606
3090
4485
5445
|
40.0
47.7
56.7
|
Male
HM
9702-0601
3480
5780
6530
|
40.0
48.6
56.6
|
Male
HM
9702-0602
3165
5060
6660
|
40.0
48.3
57.1
|
Male
HM
9703-0502
2670
5420
7220
|
40.0
48.3
57.1
|
Male
HM
9703-0503
4100
6740
8330
|
40.0
47.4
56.4
|
Male
HM
9703-0504
3435
6000
7930
|
40.0
48.1
57.1
|
Male
HM
9704-0502
3285
5220
6560
|
40.0
48.1
56.6
|
Male
HM
9704-0503
3400
5200
6725
|
40.0
48.7
56.9
|
Male
HM
9705-0601
3400
5200
6725
|
40.0
48.3
57.3
|
Male
HM
9705-0602
3860
6227
|
40.0
48.0
|
Male
HM
9706-0601
3152
5105
6545
|
40.0
47.4
57.7
|
Male
HM
9706-0602
3557
5175
7315
|
40.0
47.4
57.7
|
Male
HM
9706-0603
3192
5070
6970
|
40.0
47.9
56.7
|
Male
HM
9706-0604
3461
4225
5525
|
40.0
48.0
57.1
|
Male
HM
9706-0605
3870
6220
7660
|
40.0
48.1
56.4
|
Male
HM
9706-0606
4315
5975
6720
|
40.0
48.3
56.6
|
Male
HM
9707-0601
3263
4730
5825
|
40.0
48.1
57.0
|
Male
HM
9707-0602
3206
4515
6220
|
40.0
48.1
57.7
|
Male
HM
9707-0603
4256
6930
8810
|
40.0
48.0
57.0
|
Male
HM
9707-0604
3419
5460
6130
|
40.0
48.0
56.7
|
Male
HM
9707-0605
3433
|
40.0
|
Male
HM
9707-0606
3603
5825
|
40.0
48.4
|
Male
HM
9707-0607
3569
5410
6870
|
40.0
47.9
56.9
|
Male
HM
9707-0608
3348
5135
6370
|
40.0
48.0
57.0
|
Male
HM
9707-0609
3348
|
40.0
|
Male
HM
9708-0601
3064
5220
6595
|
40.0
47.6
56.4
|
Male
HM
9708-0602
4085
|
40.0
|
Male
HM
9708-0603
3319
5135
6327
|
40.0
48.4
57.1
|
Male
HM
9708-0604
3291
|
40.0
|
Male
HM
9708-0605
3796
|
40.0
|
Male
HM
9708-0606
4020
4645
5405
|
40.0
48.4
57.1
|
Male
HM
9708-0607
3333
4043
5180
|
40.0
47.9
56.7
|
Male
HM
9709-0505
3400
|
40.0
|
Female
Control
9698-0003*
Weight (g)
1020
1050
1070
1080
1080
1060
1080
1070
5.6
|
Age (weeks pca)
31.1
31.3
31.1
31.6
31.7
31.9
32.0
32.1
|
Female
Control
9699-0001
Weight (g)
1464
1672
1862
2000
2145
24.1
2610
4369
5220
|
Age (weeks pca)
32.7
33.7
34.7
35.7
36.7
39.7
47.9
56.9
|
Female
Control
9699-0003
Weight (g)
1473
1629
1860
2497
37.3
2780
4596
5816
|
Age (weeks pca)
34.0
35.0
36.0
38.0
40.0
48.0
57.0
|
Female
Control
9701-0003
Weight (g)
1480
1633
1903
1975
2292
29.1
2675
4165
5200
|
Age (weeks pca)
34.6
35.6
36.6
37.3
38.6
40.6
48.6
55.6
|
Female
Control
9701-0005
Weight (g)
1174
1366
1555
1745
1976
28.3
3175
5140
6280
|
Age (weeks pca)
30.7
31.7
32.7
33.7
34.7
39.7
48.4
56.4
|
Female
Control
9701-0008
Weight (g)
1391
1569
1898
2198
2406
41.1
2980
4425
5815
|
Age (weeks pca)
34.3
35.3
36.4
37.3
37.9
40.4
47.4
56.4
|
Female
Control
9701-0011
Weight (g)
1050
1254
1492
1756
2044
36.6
2870
4420
5505
|
Age (weeks pca)
30.6
31.4
32.4
33.4
34.4
39.7
48.6
57.4
|
Female
Control
9702-0002
Weight (g)
1222
1371
1570
1750
1995
2390
29.4
3380
4900
|
Age (weeks pca)
31.7
32.7
34.1
35.1
36.0
37.1
40.4
47.6
|
Female
Control
9702-0004
Weight (g)
1454
1555
1840
2530
31.6
3600
5160
6900
|
Age (weeks pca)
31.0
31.9
33.1
36.0
39.9
47.7
56.7
|
Female
Control
9702-0010
Weight (g)
1775
2065
2410
2645
42.2
3060
4820
6690
|
Age (weeks pca)
34.0
35.0
36.0
37.0
39.9
48.3
57.6
|
Female
Control
9703-0002
Weight (g)
1170
1250
1390
1570
1825
2130
26.4
3210
4750
|
Age (weeks pca)
29.1
30.4
31.3
32.4
33.4
34.3
39.6
47.4
|
Female
Control
9703-0005
Weight (g)
1420
1590
1765
1900
2220
29.5
2610
4330
5640
|
Age (weeks pca)
31.4
32.3
33.3
33.9
35.3
37.3
46.0
55.0
|
Female
Control
9703-0008
Weight (g)
1495
1715
2095
2445
2685
48.3
3360
4780
6410
|
Age (weeks pca)
33.0
34.0
35.0
36.0
36.6
40.1
47.7
56.1
|
Female
Control
9705-0004
Weight (g)
1120
1290
1490
1660
28.3
2722
4085
5646
|
Age (weeks pca)
31.3
32.3
33.3
34.0
39.7
46.6
55.0
|
Female
Control
9706-0003
Weight (g)
1515
1673
1965
2330
37.9
|
Age (weeks pca)
35.1
36.3
37.1
38.3
|
Female
Control
9706-0005
Weight (g)
1485
1610
1805
2150
31.7
2740
4165
5305
|
Age (weeks pca)
33.0
33.7
34.7
36.0
40.0
48.1
57.3
|
Female
Control
9706-0009
Weight (g)
1525
1620
1960
31.6
3640
5495
7225
|
Age (weeks pca)
32.3
32.9
34.3
40.3
47.6
53.4
|
Female
Control
9706-0010
Weight (g)
1905
2185
56.0
3655
5390
6535
|
Age (weeks pca)
34.3
35.0
40.0
48.4
56.7
|
Female
Control
9706-0013
Weight (g)
1185
1270
1585
1810
31.1
2680
3800
|
Age (weeks pca)
31.6
32.4
33.6
34.6
40.1
48.4
|
Female
Control
9706-0016
Weight (g)
1510
1765
1935
32.6
3320
4535
5297
|
Age (weeks pca)
32.0
33.1
33.9
40.7
48.7
56.6
|
Female
Control
9707-0003
Weight (g)
1465
1505
1655
2010
2325
2765
30.2
3110
4125
4995
|
Age (weeks pca)
32.0
32.6
33.6
35.3
36.4
38.3
40.1
48.1
57.1
|
Female
Control
9707-0006
Weight (g)
1866
3430
3430
41.2
3430
5385
7250
|
Age (weeks pca)
34.6
40.0
40.0
40.0
48.9
57.3
|
Female
Control
9707-1006
Weight (g)
1815
3330
3330
39.9
3330
5490
6920
|
Age (weeks pca)
34.6
40.0
40.0
40.0
48.9
57.3
|
Female
Control
9708-0001
Weight (g)
1410
1600
1850
2050
27.2
2910
4734
|
Age (weeks pca)
33.4
34.4
35.4
36.9
40.6
48.4
|
Female
Control
9708-0003
Weight (g)
940.0
970.0
4.3
|
Age (weeks pca)
30.0
31.0
|
Female
Control
9708-0008
Weight (g)
1380
1605
1860
2180
33.1
2582
4110
5361
|
Age (weeks pca)
32.9
33.7
34.9
36.3
39.3
47.4
57.1
|
Female
Control
9709-0002
Weight (g)
1980
2225
2400
30.0
|
Age (weeks pca)
32.7
33.7
34.7
|
Female
Control
9709-0005
Weight (g)
1175
1425
1665
1945
2200
32.3
2975
4700
5900
|
Age (weeks pca)
31.9
33.3
34.6
35.6
36.3
39.6
48.4
56.7
|
Female
Control
9712-0005
Weight (g)
972.0
1145
1290
1490
1695
25.6
2930
4450
5880
|
Age (weeks pca)
29.1
30.1
31.1
32.1
33.1
40.3
47.6
57.1
|
Female
Control
9712-0006
Weight (g)
1203
1358
1585
1790
28.4
3030
4560
6230
|
Age (weeks pca)
31.9
32.9
33.9
34.9
39.7
48.0
57.0
|
Female
Control
9743-0003
Weight (g)
1300
1520
1740
1890
24.0
4000
5160
|
Age (weeks pca)
31.6
33.4
34.1
35.1
48.4
57.4
|
Female
Control
9746-0001
Weight (g)
1420
1740
2075
2320
2625
42.7
3170
4145
5192
|
Age (weeks pca)
32.6
33.6
34.6
35.6
36.6
39.7
47.6
56.6
|
Female
DHA
9698-0004
Weight (g)
1410
1650
1890
2140
34.7
3787
4795
6291
|
Age (weeks pca)
30.1
31.1
32.1
33.1
40.0
48.0
57.0
|
Female
DHA
9698-0006
Weight (g)
1110
1240
1420
1720
28.7
|
Age (weeks pca)
30.7
31.7
32.7
33.7
|
Female
DHA
9698-0009
Weight (g)
1205
1310
1520
1630
2020
|
Age (weeks pca)
30.3
31.4
32.4
33.1
34.9
|
Female
DHA
9698-0307
Weight (g)
1790
2110
2450
29.7
3135
5185
6695
|
Age (weeks pca)
34.4
35.7
37.6
39.4
47.4
56.4
|
Female
DHA
9699-0002
Weight (g)
1313
1477
1669
1929
2380
36.9
3177
5787
7093
|
Age (weeks pca)
32.9
33.9
34.9
35.9
36.9
39.7
47.7
56.7
|
Female
DHA
9700-0001
Weight (g)
1580
1820
2050
2295
2500
34.5
3210
5110
6300
|
Age (weeks pca)
32.4
33.4
34.3
35.3
36.3
40.1
48.1
57.1
|
Female
DHA
9701-0001
Weight (g)
1300
1356
1586
1924
2125
34.2
2910
4325
5625
|
Age (weeks pca)
33.0
34.0
35.0
36.0
36.6
39.6
48.0
57.0
|
Female
DHA
9701-0004
Weight (g)
1108
1261
1441
1671
1897
28.4
3020
4855
6040
|
Age (weeks pca)
30.7
31.7
32.7
33.7
34.7
39.7
48.4
56.4
|
Female
DHA
9701-0012
Weight (g)
1674
1928
2151
2311
2685
2685
30.1
2685
|
Age (weeks pca)
34.9
35.9
36.9
37.6
39.6
39.6
39.6
|
Female
DHA
9701-0014
Weight (g)
1422
1631
1858
2455
37.2
2970
4605
5140
|
Age (weeks pca)
33.9
34.9
35.9
37.9
39.9
47.7
56.9
|
Female
DHA
9702-0001
Weight (g)
1780
2115
2390
3000
35.8
3850
5610
6600
|
Age (weeks pca)
31.6
32.9
33.9
36.4
40.0
49.6
57.0
|
Female
DHA
9702-0006
Weight (g)
1850
2005
2650
2650
27.3
2650
4450
6020
|
Age (weeks pca)
35.4
36.1
39.6
39.6
39.6
48.4
56.4
|
Female
DHA
9702-0007
Weight (g)
1285
1459
1780
1965
2035
29.6
|
Age (weeks pca)
31.1
32.1
33.6
34.4
34.9
|
Female
DHA
9702-0008
Weight (g)
1605
1930
3540
3540
51.3
3540
5920
7820
|
Age (weeks pca)
34.1
35.1
39.6
39.6
39.6
47.6
57.1
|
Female
DHA
9703-0003
Weight (g)
1255
1355
1535
1845
2150
34.8
2430
4130
5010
|
Age (weeks pca)
34.4
35.1
36.1
37.1
38.1
39.4
48.1
57.1
|
Female
DHA
9703-0004
Weight (g)
1170
1340
1550
1795
2225
33.9
2870
4610
6490
|
Age (weeks pca)
32.6
33.3
34.3
35.3
37.0
39.4
48.1
57.1
|
Female
DHA
9703-0009
Weight (g)
1570
1830
2095
2395
2655
34.6
3160
4480
5570
|
Age (weeks pca)
33.3
34.3
35.1
36.3
37.9
40.4
48.4
58.0
|
Female
DHA
9704-0004
Weight (g)
1440
1670
1740
30.5
3100
5830
8630
|
Age (weeks pca)
33.6
34.6
35.0
40.0
48.0
57.0
|
Female
DHA
9704-0005
Weight (g)
1050
1310
1490
1700
1890
30.0
3360
4860
6100
|
Age (weeks pca)
29.7
30.9
31.7
32.7
33.7
39.6
48.0
57.0
|
Female
DHA
9705-0001
Weight (g)
1220
1370
1590
1880
2098
31.9
3092
4795
5986
|
Age (weeks pca)
32.7
33.6
34.7
35.7
36.7
40.1
48.1
57.1
|
Female
DHA
9706-0006
Weight (g)
1270
1405
1630
1930
31.7
2705
4145
5320
|
Age (weeks pca)
33.0
33.7
34.7
36.0
40.0
48.1
57.3
|
Female
DHA
9706-0008
Weight (g)
990.0
1188
1345
1485
23.0
2120
|
Age (weeks pca)
33.4
34.6
35.7
36.4
39.9
|
Female
DHA
9706-0012
Weight (g)
1610
1830
2130
2280
32.5
3530
4790
|
Age (weeks pca)
31.6
32.4
33.6
34.6
40.1
48.4
|
Female
DHA
9706-0014
Weight (g)
1080
1170
1395
1560
1804
26.2
3295
5600
7675
|
Age (weeks pca)
31.3
32.6
33.4
34.4
35.3
40.6
49.4
58.0
|
Female
DHA
9707-0004
Weight (g)
1635
1771
2850
38.1
3045
4595
5765
|
Age (weeks pca)
34.0
35.0
38.7
40.0
48.0
57.0
|
Female
DHA
9707-0308
Weight (g)
2005
3440
3440
42.2
3440
4800
6360
|
Age (weeks pca)
34.4
39.3
39.3
39.3
47.3
57.7
|
Female
DHA
9708-0004
Weight (g)
1460
1665
1955
2280
2485
38.1
|
Age (weeks pca)
32.6
33.6
34.6
35.6
36.6
|
Female
DHA
9708-0006
Weight (g)
1485
1775
2110
2380
39.5
3010
4620
6530
|
Age (weeks pca)
33.7
34.7
35.7
37.0
40.1
48.1
57.0
|
Female
DHA
9709-0001
Weight (g)
1250
1490
1755
1970
2250
2520
33.8
3500
|
Age (weeks pca)
29.6
31.0
32.0
33.0
34.0
35.0
40.1
|
Female
DHA
9709-0003
Weight (g)
1540
1725
2015
2155
30.5
2580
4080
5420
|
Age (weeks pca)
34.4
35.4
36.4
37.4
40.3
47.7
57.1
|
Female
DHA
9712-0001
Weight (g)
987.0
1120
1270
1470
1685
24.9
2940
3980
5250
|
Age (weeks pca)
30.0
31.0
32.0
33.0
34.0
40.1
48.1
57.1
|
Female
DHA
9712-0002
Weight (g)
1060
1230
1430
26.4
|
Age (weeks pca)
32.7
33.7
34.7
26.4
|
Female
DHA
9712-0007
Weight (g)
1082
1230
1440
1650
27.3
2425
4250
5340
|
Age (weeks pca)
32.7
33.7
34.7
35.7
39.7
47.9
56.9
|
Female
DHA
9743-0001
Weight (g)
1000
1170
1470
1800
1930
33.5
4140
5400
|
Age (weeks pca)
32.1
33.1
34.4
35.7
39.7
47.9
56.9
|
Female
DHA
9743-0002
Weight (g)
1380
1570
1845
1975
29.7
4540
5160
|
Age (weeks pca)
32.1
33.3
34.1
35.1
48.4
57.4
|
Female
DHA + ARA
9698-0001
Weight (g)
1550
1690
2000
2380
37.1
3530
5348
6582
|
Age (weeks pca)
31.6
32.6
33.6
34.9
40.0
47.7
56.7
|
Female
DHA + ARA
9698-0002
Weight (g)
1580
1870
2130
2260
31.8
3241
|
Age (weeks pca)
32.6
3.37
34.6
35.7
40.7
|
Female
DHA + ARA
9699-0004
Weight (g)
985.0
1122
1283
1536
1788
28.9
3177
5107
6979
|
Age (weeks pca)
31.0
32.0
33.0
34.0
35.0
41.3
48.3
57.3
|
Female
DHA + ARA
9699-0005
Weight (g)
1330
1542
1688
2000
2330
35.1
4029
6752
8341
|
Age (weeks pca)
31.9
32.9
33.9
34.9
35.9
40.3
48.1
57.1
|
Female
DHA + ARA
9700-0002
Weight (g)
1315
1525
1885
2035
2220
2480
31.9
3340
4930
6420
|
Age (weeks pca)
30.3
31.3
32.3
33.3
34.1
35.6
40.3
48.1
57.1
|
Female
DHA + ARA
9701-0002
Weight (g)
1398
1609
1887
2210
2420
37.8
2930
5115
6525
|
Age (weeks pca)
33.4
34.4
35.4
36.4
37.4
39.4
48.4
56.4
|
Female
DHA + ARA
9701-0006
Weight (g)
1720
1859
2113
2456
2728
38.3
3600
5045
6270
|
Age (weeks pca)
32.3
33.3
34.3
35.3
36.1
40.3
48.0
57.3
|
Female
DHA + ARA
9701-0007
Weight (g)
1469
1427
1590
1982
2227
29.8
2680
4935
6955
|
Age (weeks pca)
33.7
34.9
35.7
36.7
37.7
39.9
47.9
56.9
|
Female
DHA + ARA
9701-0010
Weight (g)
1488
1703
1978
2234
2433
2759
34.6
3500
5545
|
Age (weeks pca)
32.3
33.4
34.4
35.3
36.1
37.7
41.1
48.4
|
Female
DHA + ARA
9701-0013
Weight (g)
1841
2019
35.6
4545
5550
|
Age (weeks pca)
33.0
33.7
48.7
57.4
|
Female
DHA + ARA
9702-0003
Weight (g)
1293
1488
1820
2155
2400
39.9
4190
6220
7500
|
Age (weeks pca)
30.1
31.1
32.1
33.4
34.1
40.0
48.4
56.9
|
Female
DHA + ARA
9702-0005
Weight (g)
1895
2060
2300
2525
2710
29.9
3025
4300
5340
|
Age (weeks pca)
34.0
35.0
36.0
37.0
38.0
40.0
47.4
56.4
|
Female
DHA + ARA
9702-0009
Weight (g)
1725
2000
2230
2595
2655
40.9
2905
4680
6410
|
Age (weeks pca)
34.0
35.0
36.0
37.0
37.3
39.9
48.3
57.6
|
Female
DHA + ARA
9703-0001
Weight (g)
1145
1255
1450
1680
1955
28.9
3030
4250
5420
|
Age (weeks pca)
31.3
32.1
33.1
34.3
35.3
41.0
48.1
57.3
|
Female
DHA + ARA
9703-0006
Weight (g)
1865
2200
2560
2880
49.1
3600
5400
6650
|
Age (weeks pca)
34.0
35.0
35.9
37.0
40.0
48.1
56.7
|
Female
DHA + ARA
9703-0007
Weight (g)
1390
1495
1620
1880
2030
2240
27.4
2850
4190
5850
|
Age (weeks pca)
32.0
33.1
34.0
35.0
35.7
36.6
40.0
47.9
56.7
|
Female
DHA + ARA
9704-0002
Weight (g)
960.0
1090
1200
1370
1570
1780
2070
26.7
3110
5150
6800
|
Age (weeks pca)
29.0
30.0
30.9
31.9
32.9
33.9
34.9
40.0
48.0
57.0
|
Female
DHA + ARA
9704-0003
Weight (g)
1690
1840
30.0
4000
5400
6640
|
Age (weeks pca)
32.7
33.4
40.0
48.0
57.0
|
Female
DHA + ARA
9705-0003
Weight (g)
1760
2260
2500
2920
49.8
3376
5107
6894
|
Age (weeks pca)
34.4
35.7
36.6
37.7
39.9
48.4
56.9
|
Female
DHA + ARA
9705-0005*
Weight (g)
1075
1120
1185
1280
1310
1310
1265
1350
1380
22.1
2600
4000
5050
|
Age (weeks pca)
31.1
31.4
31.7
32.1
32.4
32.7
33.0
33.3
33.4
40.4
48.0
57.0
|
Female
DHA + ARA
9706-0001
Weight (g)
1290
1515
1685
2060
34.5
4100
6550
7655
|
Age (weeks pca)
31.7
32.9
33.7
34.9
40.1
48.6
56.7
|
Female
DHA + ARA
9706-0002
Weight (g)
1395
1710
1884
2275
34.8
28.45
4645
5550
|
Age (weeks pca)
31.9
33.0
33.9
35.4
40.3
48.9
57.3
|
Female
DHA + ARA
9706-0004
Weight (g)
1550
1705
2050
36.1
2645
4225
4935
|
Age (weeks pca)
36.7
37.6
38.7
41.7
49.7
58.0
|
Female
DHA + ARA
9706-0007
Weight (g)
1235
1490
1820
1930
34.3
2505
|
Age (weeks pca)
33.4
34.6
35.7
36.4
40.3
|
Female
DHA + ARA
9706-0011
Weight (g)
1900
2105
41.0
3430
5175
6140
|
Age (weeks pca)
34.3
35.0
40.0
48.4
56.7
|
Female
DHA + ARA
9706-0015
Weight (g)
1670
1975
2210
41.6
3005
4465
5810
|
Age (weeks pca)
34.6
35.6
36.4
40.9
48.4
57.6
|
Female
DHA + ARA
9706-0017
Weight (g)
1465
1700
1895
2170
33.4
|
Age (weeks pca)
32.3
33.4
34.3
35.3
|
Female
DHA + ARA
9707-0002
Weight (g)
1775
2240
2385
2610
33.2
|
Age (weeks pca)
34.3
36.0
36.9
37.9
|
Female
DHA + ARA
9708-0002
Weight (g)
1535
1700
1980
2200
32.5
2724
4645
6315
|
Age (weeks pca)
33.0
34.0
35.0
36.0
38.1
47.6
55.4
|
Female
DHA + ARA
9708-0005
Weight (g)
1125
1345
1610
1980
40.4
3121
5855
7875
|
Age (weeks pca)
32.4
33.4
34.4
35.4
39.4
47.4
57.4
|
Female
DHA + ARA
9708-0007
Weight (g)
1200
1440
1680
1975
36.6
|
Age (weeks pca)
31.3
32.3
33.3
34.3
|
Female
DHA + ARA
9709-0004
Weight (g)
1350
1560
1885
2250
2475
37.0
3295
5250
6685
|
Age (weeks pca)
31.9
33.3
34.6
35.6
36.3
39.7
48.4
56.7
|
Female
DHA + ARA
9712-0003
Weight (g)
1283
1410
1590
1850
2010
40.0
48.2
57.5
|
Age (weeks pca)
32.0
33.0
34.0
35.0
36.0
40.0
48.2
57.5
|
Female
DHA + ARA
9712-0004
Weight (g)
1575
1780
1890
2080
2530
29.7
3220
4920
6600
|
Age (weeks pca)
33.0
34.0
34.6
35.6
37.6
|
Female
DHA + ARA
9712-0008
Weight (g)
1590
1780
1990
2475
37.2
2960
4470
5760
|
Age (weeks pca)
34.0
35.0
35.8
37.4
40.1
48.1
57.1
|
Female
DHA + ARA
9746-0002
Weight (g)
1249
1429
1597
1814
2110
30.1
2680
4010
5362
|
Age (weeks pca)
32.7
33.7
34.7
35.7
36.7
39.9
46.9
56.9
|
Female
HM
9698-0501
3546
4880
|
40.0
48.3
|
Female
HM
9698-0502
3518
5972
|
40.0
47.9
|
Female
HM
9698-0503
3390
4213
5319
|
40.0
48.3
57.1
|
Female
HM
9698-0504
3383
5234
6667
|
40.0
48.7
57.9
|
Female
HM
9698-0505
3646
4638
5653
|
40.0
48.3
57.0
|
Female
HM
9699-0601
2582
4766
5731
|
40.0
49.0
57.0
|
Female
HM
9699-0602
4284
4823
5986
|
40.0
48.0
57.0
|
Female
HM
9699-0603
3716
4482
5674
|
40.0
47.7
56.7
|
Female
HM
9699-0604
3660
4738
6355
|
40.0
48.0
57.0
|
Female
HM
9699-0605
3433
5671
7603
|
40.0
48.4
57.6
|
Female
HM
9701-0501
3884
5630
6450
|
40.0
47.7
57.7
|
Female
HM
9701-0502
3858
5420
6700
|
40.0
48.6
57.6
|
Female
HM
9701-0503
3430
4265
5085
|
40.0
47.4
57.4
|
Female
HM
9701-0504
3317
5020
6230
|
40.0
48.1
57.1
|
Female
HM
9702-0501
3302
5540
6630
|
40.0
47.7
56.7
|
Female
HM
9702-0502
2658
5310
6800
|
40.0
47.4
57.1
|
Female
HM
9702-0503
2895
3430
4530
|
40.0
47.7
57.4
|
Female
HM
9702-0504
3401
5390
6270
|
40.0
48.0
57.4
|
Female
HM
9702-0505
3141
4210
5320
|
40.0
47.9
57.0
|
Female
HM
9702-0506
3762
6040
7600
|
40.0
48.9
57.4
|
Female
HM
9702-0507
2718
4050
4940
|
40.0
48.9
57.4
|
Female
HM
9702-0508
2927
4240
5860
|
40.0
47.4
57.0
|
Female
HM
9703-0501
4085
5260
6360
|
40.0
48.1
57.1
|
Female
HM
9703-0505
3390
5760
7670
|
40.0
48.3
57.3
|
Female
HM
9703-0506
3405
6170
7490
|
40.0
47.9
56.9
|
Female
HM
9703-0507
3085
5090
6550
|
40.0
48.0
6550
|
Female
HM
9704-0501
3194
4700
5880
|
40.0
48.1
57.4
|
Female
HM
9705-0501
3120
4500
5702
|
40.0
48.1
57.1
|
Female
HM
9705-0502
4080
6327
7348
|
40.0
48.3
57.3
|
Female
HM
9706-0501
3396
5000
6645
|
40.0
48.3
58.1
|
Female
HM
9706-0502
3041
4315
5525
|
40.0
47.7
57.6
|
Female
HM
9707-0501
4653
5515
6770
|
40.0
47.9
56.6
|
Female
HM
9707-0502
3419
5500
7080
|
40.0
48.0
57.1
|
Female
HM
9707-0503
3773
5785
7675
|
40.0
47.9
56.9
|
Female
HM
9707-0505
3716
|
40.0
|
Female
HM
9708-0501
3688
5440
6890
|
40.0
48.1
57.6
|
Female
HM
9708-0502
3454
5192
5950
|
40.0
48.1
57.4
|
Female
HM
9708-0503
2977
5165
7040
|
40.0
48.1
57.4
|
Female
HM
9708-0504
3864
5660
6705
|
40.0
48.4
57.4
|
Female
HM
9708-0505
3831
5800
7435
|
40.0
47.7
57.6
|
Female
HM
9709-0501
3550
|
40.0
|
Female
HM
9709-0502
3715
5205
6100
|
40.0
48.0
56.9
|
Female
HM
9709-0503
3195
|
40.0
|
Female
HM
9709-0504
3190
4590
|
40.0
48.3
|
Female
HM
9709-0506
3505
4500
5910
|
40.0
48.0
57.1
|
|
Growth
|
Rate
Regi-
Sub-
Vari-
|
Gender
men
ject
able
Wgt1
Wgt2
Wgt3
Wgt4
Wgt5
Wgt6
Wgt7
Wgt8
Wgt9
Wgt10
Wgt11
Wgt12
Wgt13
Wgt14
Wgt15
Wgt16
Wgt17
Wgt18
g/day
|
|
Male
Control
9712-
Weight
1245
1221
1245
1291
1294
1330
1369
1402
1433
1448
1465
26.1
|
(g)
|
0301
Age
31.6
31.7
31.9
32.0
32.1
32.3
32.4
32.6
32.7
32.9
33.0
|
(weeks
|
pca)
|
Male
DHA
9707-
Weight
1649
1675
1699
1732
1778
1811
1858
1882
1938
1994
2030
2075
39.6
|
(g)
|
0307
Age
32.4
32.6
32.7
32.9
33.0
33.1
33.3
33.4
33.6
33.7
33.9
34.0
|
(weeks
|
pca)
|
Female
Control
9698-
Weight
1020
1050
1070
1080
1080
1060
1080
1070
5.6
|
|
0003
Age
31.1
31.3
31.4
31.6
31.7
31.9
32.0
32.1
|
(weeks
|
pca)
|
Female
DHA +
9705-
Weight
1075
1120
1185
1280
1310
1310
1265
1350
1380
1440
1450
1510
1515
1565
1585
1640
1680
1670
22.1
|
(g)
|
ARA
0005
Age
31.1
31.4
31.7
32.1
32.4
32.7
33.0
33.3
33.4
33.7
33.9
34.0
34.1
34.3
34.4
34.6
34.7
34.9
|
(weeks
|
pca)
|
|
Claims
- 1. A method for enhancing the growth of preterm infants comprising administering to said infants a growth enhancing amount of DHA and ARA.
- 2. The method of claim 1 wherein DHA and ARA are supplemented into infant formula.
- 3. The method of claim 1 wherein the ratio of ARA:DHA is 1:2 to 5:1.
- 4. The method of claim 1 wherein the ratio of ARA:DHA is 1.1 to 3:1.
- 5. The method of claim 1 wherein the ratio of ARA:DHA is about 2:1.
- 6. The method of claim 2 wherein the infant formula comprises DHA in an amount of about 2 mg/100 kcal to about 50 mg/100 kcal and ARA in an amount of about 4 mg/100 kcal to about 100 mg/100 kcal.
- 7. The method of claim 2 wherein the infant formula comprises DHA in an amount of about 5 mg/100 kcal to about 33 mg/100 kcal and ARA in an amount of about 10 mg/100 kcal to about 67 mg/100 kcal.
- 8. The method of claim 2 wherein the infant formula comprises DRA in an amount of about 15 mg/100 kcal to about 20 mg/100 kcal and ARA in an amount of about 30 mg/100 kcal to about 40 mg/100 kcal.
- 9. The method of claim 1 wherein the amount of time to achieve growth equivalent to normal terms breast fed infants is less than 9 months corrected age.
- 10. The method of claim 1 wherein the amount of time to achieve growth equivalent to normal terms breast fed infants is less than 6 months corrected age.
- 11. The method of claim 1 wherein the amount of time to achieve growth equivalent to normal terms breast fed infants is less than 4 months corrected age.
- 12. The method of claim 1 wherein the amount of time to achieve growth equivalent to normal terms breast fed infants is less than 2 months corrected age.
- 13. The method of claim 1 wherein the amount of time to achieve growth equivalent to normal terms breast fed infants is no greater than term corrected age.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
PCT/US98/10566 |
3/20/1998 |
WO |
|