Prematurity
Conditions
Keywords
Premature Infants, DHA(docosahexaenoic acid), DHA deficit
Brief summary
The purpose of this study is to understand if the DHA gap can be corrected by giving a daily dose of DHA oil to preterm babies. DHA is an essential omega-3 fatty acid, which means our body cannot make DHA. We have to take it in through our diet. DHA is important for normal brain and eye health and it may also decrease inflammation. This is important for premature babies because they are at a greater risk for getting diseases related to inflammation, especially in their lungs, eyes and intestines. Since DHA is so important for normal growth, you will find DHA naturally in breast milk and it is now added to infant formula. But the amount in breast milk and infant formula is about half of what your infant should expect to get in the womb (about 13-29mg per day in breast milk vs. 50-75mg per day in the womb). Very premature babies are at an even greater disadvantage because they cannot always eat very much right away and that is the only way they can get essential fatty acids in their body. This means premature babies are getting less DHA than they would in the womb and then the DHA gap continues for a longer period of time. This gap also comes at a time when their brain is growing most rapidly and their bodies need it the most. This trial is designed to see if giving DHA, even before the baby can take food orally, will raise his/her DHA blood levels to those of normal term babies.
Detailed description
Docosahexaenoic acid (DHA) is an essential fatty acid (FA) important for health and neurodevelopment. Premature infants are at risk of DHA deficiency and circulating levels directly correlate with health outcomes. Most supplementation strategies have focused on increasing DHA content in mother's milk or infant formula. However, extremely premature infants may not reach full feedings for weeks and commercially available parenteral lipid emulsions do not contain preformed DHA, so blood levels decline rapidly after birth. Our objective is to develop a DHA supplementation strategy to overcome these barriers. This single-center, double-blind, randomized, controlled trial determined feasibility, tolerability and efficacy of daily enteral DHA supplementation (50 mg/day) in addition to standard nutrition for preterm infants (24-34 weeks gestational age) beginning in the first week of life. Blood FA levels will be analyzed at baseline, full feedings and near discharge in DHA or placebo supplemented preterm infants. Term peers will also have blood FA levels analyzed for comparison. Growth, feeding tolerance and adverse outcomes (NEC, intraventricular hemorrhage (IVH), thrombocytopenia, sepsis) will be evaluated. Study progress and safety will be monitored by an external Data Safety Monitoring Board (DSMB). Overall, the study aims to determine if daily enteral DHA supplementation is feasible and alleviates deficiency in premature infants.
Interventions
DIETARY_SUPPLEMENTDHA oil
Therapy Group:DHA oil administered at 50 mg/d (0.18ml) as an oil emulsion enterally with feedings or by gavage tube if the infant has one.
DIETARY_SUPPLEMENT(MCT) Control oil
Placebo Group:MCT oil administered at 0.18 ml as an oil emulsion enterally with feedings or by gavage tube if the infant has one.
Sponsors
The Gerber Foundation
Sanford Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
24 Weeks to 33 Weeks
Healthy volunteers
Yes
Inclusion criteria
* Preterm infants between 24 and 33 6/7 weeks gestation * must be less than or equal to 1 week of age
Exclusion criteria
* infants who are considered by the medical team to be non-viable * infants with multiple or severe congenital anomalies such as gastroschisis, congenital chylothorax or other illnesses that do not allow a feeding tube to be placed or utilized at 7 days of age. * term infants: who are born to mothers with diabetes or are small for gestational age (SGA-less than the 10th% for adjusted gestational age * All families consented for this study will need to be able to read and write English * Mother must be 18 years of age or older * Taking Omegaven
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility and Tolerability of Daily Enteral DHA Oil - Head Circumference | 30 days from birth | A linear mixed model was used to explore head circumference over time. |
| Feasibility and Tolerability of Daily Enteral DHA Oil - Weight Change | 30 days from birth | A linear mixed model was used to explore weight over time. |
| Long Chain Polyunsaturated Fatty Acid (LCPUFA) Levels - Docosahexaenoic Acid (DHA) Levels in Whole Blood | At baseline (enrollment, < 1 week of age), full feedings, discharge | Linear mixed models were also used to examine the association between each FA of interest and treatment group over time. Since only three time points were available for FA measurement, only a random intercept was included in the models. For these models, the random effect for multiples was again found to be not needed and removed. Primary outcome variables for this analysis included LNA, ALA, ARA and DHA. Only early/late preterm status was included in the model as a covariate since this was a stratification variable. Continuous dependent variables were transformed using the natural logarithm as needed to meet the assumptions of the regression model (this included LNA and ALA). |
| Feasibility and Tolerability of Daily Enteral DHA Oil - Length Change | 30 days from birth | A linear mixed model was used to explore length over time. |
| Days to Reach Full Enteral Feedings and Days on Study Oil. | From enrollment until the infant reaches full feed or is discharged from the NICU, whichever comes first, assessed up to 50 days. | This study was designed to determine feasibility and tolerability of enteral DHA supplementation, but was not intended to determine the effects of DHA on health related outcomes. Tolerability was measured by days to reach full enteral feedings, days on study oil, GA at completion of the study and postnatal growth. The days to reach full enteral feedings was defined as enteral intake of 100kcal/kg/d. Safety and tolerability was closely monitored under the oversight of an independent DSMB. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| LCPUFA Levels - Arachidonic Acid (ARA) in Whole Blood | At baseline (enrollment, <1 week of age), full feedings and discharge | Linear mixed models were also used to examine the association between each FA of interest and treatment group over time. Since only three time points were available for FA measurement, only a random intercept was included in the models. For these models, the random effect for multiples was again found to be not needed and removed. Primary outcome variables for this analysis included LNA, ALA, ARA and DHA. Only early/late preterm status was included in the model as a covariate since this was a stratification variable. Continuous dependent variables were transformed using the natural logarithm as needed to meet the assumptions of the regression model (this included LNA and ALA). |
Other
| Measure | Time frame | Description |
|---|---|---|
| LCPUFA Levels - Linoleic Acid (LNA) | Baseline, full feedings and discharge | Linear mixed models were also used to examine the association between each FA of interest and treatment group over time. Since only three time points were available for FA measurement, only a random intercept was included in the models. For these models, the random effect for multiples was again found to be not needed and removed. Primary outcome variables for this analysis included LNA, ALA, ARA and DHA. Only early/late preterm status was included in the model as a covariate since this was a stratification variable. Continuous dependent variables were transformed using the natural logarithm as needed to meet the assumptions of the regression model (this included LNA and ALA). |
| LCPUFA Levels - Alpha-linolenic Acid (ALA) in Whole Blood | Baseline (<1 week of age), full enteral feedings and discharge | Linear mixed models were also used to examine the association between each FA of interest and treatment group over time. Since only three time points were available for FA measurement, only a random intercept was included in the models. For these models, the random effect for multiples was again found to be not needed and removed. Primary outcome variables for this analysis included LNA, ALA, ARA and DHA. Only early/late preterm status was included in the model as a covariate since this was a stratification variable. Continuous dependent variables were transformed using the natural logarithm as needed to meet the assumptions of the regression model (this included LNA and ALA). |
Countries
United States
Participant flow
Recruitment details
Ninety infants, less than or equal to one week of age, were recruited from the Sanford Health Boekelheide Neonatal Intensive Care Unit (NICU) between October 2012 and March 2014.
Pre-assignment details
Preterm infants were between 24 and 33 6/7 weeks gestational age (GA) at birth. Adaptive enrollment was used to assure that infants \<28 weeks GA were enrolled over the same time period as more commonly admitted preterm infants \>28 weeks GA.
Participants by arm
| Arm | Count |
|---|---|
| DHA Supplemented Preterm infants (31) randomized to receive 50mg/d of enteral DHA supplementation | 31 |
| Placebo Supplemented Preterm infants (29) randomized to receive placebo study oil | 29 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | DHA Supplemented | Placebo Supplemented | Total |
|---|---|---|---|
| Age, Continuous | 30.69 weeks of GA STANDARD_DEVIATION 2.42 | 30.35 weeks of GA STANDARD_DEVIATION 2.46 | 30.52 weeks of GA STANDARD_DEVIATION 2.43 |
| Race/Ethnicity, Customized Hispanic | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Non-Hispanic | 28 Participants | 25 Participants | 53 Participants |
| Race/Ethnicity, Customized Unknown | 3 Participants | 4 Participants | 7 Participants |
| Region of Enrollment United States | 31 Participants | 29 Participants | 60 Participants |
| Sex: Female, Male Female | 15 Participants | 15 Participants | 30 Participants |
| Sex: Female, Male Male | 16 Participants | 14 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 31 / 31 | 29 / 29 |
| serious Total, serious adverse events | 1 / 31 | 0 / 29 |
Outcome results
Primary
Days to Reach Full Enteral Feedings and Days on Study Oil.
This study was designed to determine feasibility and tolerability of enteral DHA supplementation, but was not intended to determine the effects of DHA on health related outcomes. Tolerability was measured by days to reach full enteral feedings, days on study oil, GA at completion of the study and postnatal growth. The days to reach full enteral feedings was defined as enteral intake of 100kcal/kg/d. Safety and tolerability was closely monitored under the oversight of an independent DSMB.
Time frame: From enrollment until the infant reaches full feed or is discharged from the NICU, whichever comes first, assessed up to 50 days.
Population: Comparison between preterm groups that received either DHA oil or MCT (placebo control) oil were made.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DHA Oil | Days to Reach Full Enteral Feedings and Days on Study Oil. | Days to reach full enteral feedings | 20.00 days | Standard Deviation 8.32 |
| DHA Oil | Days to Reach Full Enteral Feedings and Days on Study Oil. | Days on Study oil | 34.00 days | Standard Deviation 19.2 |
| (MCT) Control Oil | Days to Reach Full Enteral Feedings and Days on Study Oil. | Days to reach full enteral feedings | 16.21 days | Standard Deviation 7.41 |
| (MCT) Control Oil | Days to Reach Full Enteral Feedings and Days on Study Oil. | Days on Study oil | 33.71 days | Standard Deviation 16.32 |
Comparison: All analyses used the intent-to-treat study population. A linear mixed model was used to assess differences in time to full feeds, days on study drug, and gestational age at discharge. These models included a random effect for multiples, which was maintained in the model after testing. Fixed effects included treatment and GA group for time to full feeds and days on study drug and treatment effect for gestational age at discharge.p-value: 0.0795% CI: [0.2, 28.7]Regression, Linear
Primary
Feasibility and Tolerability of Daily Enteral DHA Oil - Head Circumference
A linear mixed model was used to explore head circumference over time.
Time frame: 30 days from birth
Population: Comparison between preterm groups that received either DHA oil or MCT (placebo control) oil were made. They had DHA levels measured to be used as a reference population in our NICU.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DHA Oil | Feasibility and Tolerability of Daily Enteral DHA Oil - Head Circumference | 0.10 Centimeters per day | Standard Error 0.004 |
| (MCT) Control Oil | Feasibility and Tolerability of Daily Enteral DHA Oil - Head Circumference | 0.10 Centimeters per day | Standard Error 0.004 |
Primary
Feasibility and Tolerability of Daily Enteral DHA Oil - Length Change
A linear mixed model was used to explore length over time.
Time frame: 30 days from birth
Population: Comparison between preterm groups that received either DHA oil or MCT (placebo control) oil were made. They had DHA levels measured to be used as a reference population in our NICU.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DHA Oil | Feasibility and Tolerability of Daily Enteral DHA Oil - Length Change | 0.13 Centimeters per day | Standard Error 0.006 |
| (MCT) Control Oil | Feasibility and Tolerability of Daily Enteral DHA Oil - Length Change | 0.12 Centimeters per day | Standard Error 0.004 |
Primary
Feasibility and Tolerability of Daily Enteral DHA Oil - Weight Change
A linear mixed model was used to explore weight over time.
Time frame: 30 days from birth
Population: Comparison between preterm groups that received either DHA oil or MCT (placebo control) oil were made. They had DHA levels measured to be used as a reference population in our NICU.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DHA Oil | Feasibility and Tolerability of Daily Enteral DHA Oil - Weight Change | 18.4 Grams per day | Standard Error 0.57 |
| (MCT) Control Oil | Feasibility and Tolerability of Daily Enteral DHA Oil - Weight Change | 18.4 Grams per day | Standard Error 0.57 |
Comparison: Linear mixed models were used to explore growth over time (weight, length and head circumference). These models included a random effect for intercepts and slopes to account for subject specific growth over time as well as a random effect for possible correlation between twins and triplets present in the data set. Fixed effects included both a linear and quadratic time effect, GA at birth, treatment group, full feeds (yes/no), and interactions. Non-significant interactions were eliminated.p-value: 0.048Regression, Linear
Primary
Long Chain Polyunsaturated Fatty Acid (LCPUFA) Levels - Docosahexaenoic Acid (DHA) Levels in Whole Blood
Linear mixed models were also used to examine the association between each FA of interest and treatment group over time. Since only three time points were available for FA measurement, only a random intercept was included in the models. For these models, the random effect for multiples was again found to be not needed and removed. Primary outcome variables for this analysis included LNA, ALA, ARA and DHA. Only early/late preterm status was included in the model as a covariate since this was a stratification variable. Continuous dependent variables were transformed using the natural logarithm as needed to meet the assumptions of the regression model (this included LNA and ALA).
Time frame: At baseline (enrollment, < 1 week of age), full feedings, discharge
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DHA Oil | Long Chain Polyunsaturated Fatty Acid (LCPUFA) Levels - Docosahexaenoic Acid (DHA) Levels in Whole Blood | Full Enteral Feedings | 2.83 mol% (composition) of fat | Standard Deviation 0.5 |
| DHA Oil | Long Chain Polyunsaturated Fatty Acid (LCPUFA) Levels - Docosahexaenoic Acid (DHA) Levels in Whole Blood | Discharge | 2.87 mol% (composition) of fat | Standard Deviation 0.5 |
| DHA Oil | Long Chain Polyunsaturated Fatty Acid (LCPUFA) Levels - Docosahexaenoic Acid (DHA) Levels in Whole Blood | Baseline Comparisons | 2.91 mol% (composition) of fat | Standard Deviation 0.45 |
| (MCT) Control Oil | Long Chain Polyunsaturated Fatty Acid (LCPUFA) Levels - Docosahexaenoic Acid (DHA) Levels in Whole Blood | Full Enteral Feedings | 3.03 mol% (composition) of fat | Standard Deviation 0.54 |
| (MCT) Control Oil | Long Chain Polyunsaturated Fatty Acid (LCPUFA) Levels - Docosahexaenoic Acid (DHA) Levels in Whole Blood | Baseline Comparisons | 2.88 mol% (composition) of fat | Standard Deviation 0.68 |
| (MCT) Control Oil | Long Chain Polyunsaturated Fatty Acid (LCPUFA) Levels - Docosahexaenoic Acid (DHA) Levels in Whole Blood | Discharge | 3.55 mol% (composition) of fat | Standard Deviation 0.44 |
Secondary
LCPUFA Levels - Arachidonic Acid (ARA) in Whole Blood
Linear mixed models were also used to examine the association between each FA of interest and treatment group over time. Since only three time points were available for FA measurement, only a random intercept was included in the models. For these models, the random effect for multiples was again found to be not needed and removed. Primary outcome variables for this analysis included LNA, ALA, ARA and DHA. Only early/late preterm status was included in the model as a covariate since this was a stratification variable. Continuous dependent variables were transformed using the natural logarithm as needed to meet the assumptions of the regression model (this included LNA and ALA).
Time frame: At baseline (enrollment, <1 week of age), full feedings and discharge
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DHA Oil | LCPUFA Levels - Arachidonic Acid (ARA) in Whole Blood | Baseline | 13.21 wt:wt% of total fat in sample | Standard Deviation 2.22 |
| DHA Oil | LCPUFA Levels - Arachidonic Acid (ARA) in Whole Blood | Discharge | 14.31 wt:wt% of total fat in sample | Standard Deviation 1.26 |
| DHA Oil | LCPUFA Levels - Arachidonic Acid (ARA) in Whole Blood | Full Enteral Feedings | 14.35 wt:wt% of total fat in sample | Standard Deviation 1.51 |
| (MCT) Control Oil | LCPUFA Levels - Arachidonic Acid (ARA) in Whole Blood | Baseline | 14.89 wt:wt% of total fat in sample | Standard Deviation 1.89 |
| (MCT) Control Oil | LCPUFA Levels - Arachidonic Acid (ARA) in Whole Blood | Full Enteral Feedings | 14.87 wt:wt% of total fat in sample | Standard Deviation 1.5 |
| (MCT) Control Oil | LCPUFA Levels - Arachidonic Acid (ARA) in Whole Blood | Discharge | 13.94 wt:wt% of total fat in sample | Standard Deviation 1.67 |
Other Pre-specified
LCPUFA Levels - Alpha-linolenic Acid (ALA) in Whole Blood
Linear mixed models were also used to examine the association between each FA of interest and treatment group over time. Since only three time points were available for FA measurement, only a random intercept was included in the models. For these models, the random effect for multiples was again found to be not needed and removed. Primary outcome variables for this analysis included LNA, ALA, ARA and DHA. Only early/late preterm status was included in the model as a covariate since this was a stratification variable. Continuous dependent variables were transformed using the natural logarithm as needed to meet the assumptions of the regression model (this included LNA and ALA).
Time frame: Baseline (<1 week of age), full enteral feedings and discharge
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DHA Oil | LCPUFA Levels - Alpha-linolenic Acid (ALA) in Whole Blood | Full enteral feedings | 0.21 wt:wt% (composition) of total fat | Standard Deviation 0.13 |
| DHA Oil | LCPUFA Levels - Alpha-linolenic Acid (ALA) in Whole Blood | Baseline | 0.74 wt:wt% (composition) of total fat | Standard Deviation 0.5 |
| DHA Oil | LCPUFA Levels - Alpha-linolenic Acid (ALA) in Whole Blood | Discharge | 0.24 wt:wt% (composition) of total fat | Standard Deviation 0.13 |
| (MCT) Control Oil | LCPUFA Levels - Alpha-linolenic Acid (ALA) in Whole Blood | Baseline | 0.55 wt:wt% (composition) of total fat | Standard Deviation 0.33 |
| (MCT) Control Oil | LCPUFA Levels - Alpha-linolenic Acid (ALA) in Whole Blood | Full enteral feedings | 0.20 wt:wt% (composition) of total fat | Standard Deviation 0.11 |
| (MCT) Control Oil | LCPUFA Levels - Alpha-linolenic Acid (ALA) in Whole Blood | Discharge | 0.26 wt:wt% (composition) of total fat | Standard Deviation 0.13 |
Other Pre-specified
LCPUFA Levels - Linoleic Acid (LNA)
Linear mixed models were also used to examine the association between each FA of interest and treatment group over time. Since only three time points were available for FA measurement, only a random intercept was included in the models. For these models, the random effect for multiples was again found to be not needed and removed. Primary outcome variables for this analysis included LNA, ALA, ARA and DHA. Only early/late preterm status was included in the model as a covariate since this was a stratification variable. Continuous dependent variables were transformed using the natural logarithm as needed to meet the assumptions of the regression model (this included LNA and ALA).
Time frame: Baseline, full feedings and discharge
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DHA Oil | LCPUFA Levels - Linoleic Acid (LNA) | Baseline | 18.45 wt:wt% (composition) of fat in sample | Standard Deviation 4.51 |
| DHA Oil | LCPUFA Levels - Linoleic Acid (LNA) | Full feedings | 14.72 wt:wt% (composition) of fat in sample | Standard Deviation 2.05 |
| DHA Oil | LCPUFA Levels - Linoleic Acid (LNA) | Discharge | 15.37 wt:wt% (composition) of fat in sample | Standard Deviation 2.39 |
| (MCT) Control Oil | LCPUFA Levels - Linoleic Acid (LNA) | Baseline | 16.45 wt:wt% (composition) of fat in sample | Standard Deviation 3.39 |
| (MCT) Control Oil | LCPUFA Levels - Linoleic Acid (LNA) | Full feedings | 14.95 wt:wt% (composition) of fat in sample | Standard Deviation 2.04 |
| (MCT) Control Oil | LCPUFA Levels - Linoleic Acid (LNA) | Discharge | 16.64 wt:wt% (composition) of fat in sample | Standard Deviation 3.18 |