Susan E. Carlson - US grants

Docosahexaenoic acid (DHA, 22:6N-3) is a major component of neural and retinal membranes. Limited accumulation is associated with learning and visual acuity deficits. DHA is transmitted from mother to the fetus/infant in the last intrauterine trimester and in milk. Premature infants may receive neither form of maternal DHA, have poor DHA stores and limited DHA synthesis from linolenic acid. Nonphysiological declines in RBC DHA occur following early delivery unless DHA is fed (human milk, fish oil). Lipid supplementation studies carried out in the Newborn Center at the University of Tennessee, Memphis will be directed toward assessing the role of specific n-6 and n-3 containing lipids in membrane biochemistry, visual acuity, recognition memory, granulocyte response to stimuli and airway function. In 1987, 195 infants in this birthweight category were discharged live from the unit. A nutrition team assures consistent unit management. 1) Preterm infants at low risk for poor developmental outcomes will be randomized to receive formula with and without DHA when >110 kcal/kg/d from formula is tolerated. Biochemical and functional followup will occur to 92 wks with assessment of plasma and red blood cell phospholipid fatty acids,k tocopherol and retinol by chromatographic techniques, retinol- binding protein by radialimmunodiffusion at enrollment, 40, 48, 57, 69, 79 and 92 wks postconception; visual acuity (Teller acuity cards) at 40, 48, 57, 69, 79 and 92 wks; recognition memory (Fagan infantest for cognitive function) at 69, 79, and 92 wks, and Bayley Mental and Physical Development (MDI/PDI) at 92 wks. Stepwise regression will include biochemical (n-3 fatty acids, retinol, -tocopherol, retinol-binding protein) and maternal/ neonatal/perinatal variables such as birth wt, gestational age, age at enrollment, O2, ventilatory support, maternal age and gravida. Ophthalmic screening will identify infants with myopia, hyperopia, astigmatism, aniosometria or strabismus precluding binocular testing. 2) Soybean phosphatidylcholine and reduced ratios of eicosapentaenoate (EPA, 20:5n-3) to DHA will be fed and their effects on PMN leukocyte composition and function studied. 3) The effect of n-3 supplementation immediately after birth on respiratory function/biochemistry will be studied in very small premature infants (<1000 g birth wt) who are at greatest risk for chronic lung disease. Their n-3 status is very poor. Evidence suggests that polyunsaturated fatty acids, especially fish oil DNA and EPA, could protect against lung damage induced by artificial ventilation and oxygen administration. DHA administration in intravenous lipid and formula will begin within 48-72 hrs after birth. In 1987, 77 of 139 inborn infants (55%^) weighing less than 1000 g at birth were discharged live from the UT, Memphis, Newborn Center.

Docosahexaenoic acid (DHA, 22:6N-3) is a major component of neural and retinal membranes. Limited accumulation is associated with learning and visual acuity deficits. DHA is transmitted from mother to the fetus/infant in the last intrauterine trimester and in milk. Premature infants may receive neither form of maternal DHA, have poor DHA stores and limited DHA synthesis from linolenic acid. Nonphysiological declines in RBC DHA occur following early delivery unless DHA is fed (human milk, fish oil). Lipid supplementation studies carried out in the Newborn Center at the University of Tennessee, Memphis will be directed toward assessing the role of specific n-6 and n-3 containing lipids in membrane biochemistry, visual acuity, recognition memory, granulocyte response to stimuli and airway function. In 1987, 195 infants in this birthweight category were discharged live from the unit. A nutrition team assures consistent unit management. 1) Preterm infants at low risk for poor developmental outcomes will be randomized to receive formula with and without DHA when >110 kcal/kg/d from formula is tolerated. Biochemical and functional followup will occur to 92 wks with assessment of plasma and red blood cell phospholipid fatty acids,k tocopherol and retinol by chromatographic techniques, retinol- binding protein by radialimmunodiffusion at enrollment, 40, 48, 57, 69, 79 and 92 wks postconception; visual acuity (Teller acuity cards) at 40, 48, 57, 69, 79 and 92 wks; recognition memory (Fagan infantest for cognitive function) at 69, 79, and 92 wks, and Bayley Mental and Physical Development (MDI/PDI) at 92 wks. Stepwise regression will include biochemical (n-3 fatty acids, retinol, -tocopherol, retinol-binding protein) and maternal/ neonatal/perinatal variables such as birth wt, gestational age, age at enrollment, O2, ventilatory support, maternal age and gravida. Ophthalmic screening will identify infants with myopia, hyperopia, astigmatism, aniosometria or strabismus precluding binocular testing. 2) Soybean phosphatidylcholine and reduced ratios of eicosapentaenoate (EPA, 20:5n-3) to DHA will be fed and their effects on PMN leukocyte composition and function studied. 3) The effect of n-3 supplementation immediately after birth on respiratory function/biochemistry will be studied in very small premature infants (<1000 g birth wt) who are at greatest risk for chronic lung disease. Their n-3 status is very poor. Evidence suggests that polyunsaturated fatty acids, especially fish oil DNA and EPA, could protect against lung damage induced by artificial ventilation and oxygen administration. DHA administration in intravenous lipid and formula will begin within 48-72 hrs after birth. In 1987, 77 of 139 inborn infants (55%^) weighing less than 1000 g at birth were discharged live from the UT, Memphis, Newborn Center.

DESCRIPTION (provided by applicant): Docosahexaenoic acid (DHA) is a member of the omega-3 fatty acid family;it is found in all cell membranes, and is accumulated in especially large quantities in the retina and brain. Over the past decades, evidence has accumulated in support of the hypothesis that DHA may have an important role in pregnancy health and outcome, as well as in the postnatal development of perceptual and cognitive function in infancy. However, prior work on this topic has focused on postnatal supplementation and the amelioration of risk in premature infants;this is in contrast to evidence indicating that DHA is accumulated in the fetal brain during gestation, probably through maternal dietary intake. The current proposal is therefore based on the possibility that prenatal supplementation may be an especially efficacious means of affecting positive pregnancy and postnatal outcomes. An earlier clinical trial conducted by our research team provided a relatively low level of DHA supplementation (approximately 100 mg/day) during the last trimester of pregnancy. This supplementation produced an increase of 6 days in the duration of gestation. In addition, higher maternal RBC DHA at delivery in a subset of this population was related to infant cognitive outcomes (more mature infant attention and lower infant distractibility through 18 months of age). In the current application, we propose a Phase III Clinical Trial (randomized, double blind, placebo-controlled) with a larger supplement of DHA (600 mg/day vs 100 mg/day) and longer duration of supplementation (2 vs 1 trimester of pregnancy). This increased dosage and period of exposure is designed to increase gestation duration and intrauterine growth in the same population studied in the previous clinical trial. Reviewers of the initial submission felt the value of the study would be increased by infant followup. An extensive postnatal followup was included in the revision, designed to determine the effect of experimentally increasing maternal DHA intake on visual and cognitive outcomes in infancy and early childhood. Reviewers indicated approval of the added postnatal followup, however, they raised several new questions about compliance with capsule intake and possibly high attrition from the postnatal followup portion of the study and requested operational definitions of some measures. These have been addressed here in detail in the Introduction and body of the proposal.

DESCRIPTION (provided by applicant): Among the faculty at the University of Kansas are a group of very talented scientists pursuing women's health research in the Schools of Allied Health, Medicine, Nursing, Pharmacy and Engineering. The existence of this talented research base in women's health ignited the interest of our leadership and resulted in a successful application for a University of Kansas Medical Center (KUMC) BIRCWH Faculty Development Program (2005-2010) to formally establish and strengthen the women's health research enterprise at the University of Kansas. All four Schools and others on the main campus are partners in this proposed renewal. Interdisciplinary research among Schools is strongly emphasized. The KUMC Schools of Allied Health and Nursing are strong partners with Medicine and Pharmacy, ranking 12 and 31 in the nation for NIH funding, respectively. Mentors are In five thematic areas related to women's health: (i) Women's Reproductive Health; (ii) Maternal Health; (iii) Pathogenesis of Diseases Prevalent in Women; (iv) Drug Design, Drug Delivery, and Pharmacogenomics; and (v) Prevention, Intervention, and Health Disparities. After the grant was funded, the KUMC BIRCWH K12 program provided advanced training and career guidance for 10 junior faculty members pursuing interdisciplinary research in women's health. Four years into the funded project, 7 IWHR Scholars have received extramural funding and at least 11 junior level (assistant professor) faculty members have been hired in tenure-track positions pursuing women's health research at the University of Kansas. Our long term objective is to foster career development of junior faculty pursuing basic, translational, behavioral, clinical and health services research relevant to women's health at the University of Kansas. In addition, interactions of mentors from multiple disciplines occurring during training of IWHR Scholars has fostered new research collaborations related to women's health among established faculty and heightened awareness of the need for women's health research at our institution. Successful renewal of the KUMC BIRCWH K12 Program will continue to positively impact the pursuit of women's health research in Kansas.

? DESCRIPTION (provided by applicant): DHA intake of US adults is low and conversion of ?-linolenic acid (18:3n-3) to DHA (22:6n-3) is also low. As a result US women enter pregnancy with lower DHA status than other countries in the developed world suggesting a potential deficiency of an important nutrient that has been shown to reduce inflammation. The goal of this Phase III Clinical Trial (randomized, double-blind, and placebo-controlled) is to test the primary hypothesis that supplementing US women with 1000 mg of docosahexaenoic acid (DHA), 800 mg above the amount currently in many prenatal nutritional supplements (~200 mg) during the half of pregnancy can reduce early preterm birth (ePTB) (<34 wk. gestation). This was a favorable secondary outcomes of a US trial (RO1 HD047315, Clinical Trials.gov ID: NCT00266825) conducted at one of the proposed study sites on which the current proposal is modeled. Secondary outcomes include birth weight <1500g and pregnancy outcomes (preeclampsia, gestational diabetes, C-section delivery). We propose a Bayesian Adaptive Design with 90% power to detect the hypothesized outcomes with an estimated 938 subjects that allows the study to stop early if strong results (probability >0.995) are observed before the study is scheduled to end and places 60% of the participants on the better DHA dose. Conventional equal randomization with 90% power would require 1200 subjects, be longer, and place only 50% of the participants on the better DHA dose. The proposed study has the potential to determine if nutritional supplementation with DHA during pregnancy can reduce the incidence of ePTB, a serious public health problem with large societal and family costs. The randomization design has the potential to significantly expedite findings to the research community and clinical practice.

? DESCRIPTION (provided by applicant): DHA intake of US adults is low and conversion of ?-linolenic acid (18:3n-3) to DHA (22:6n-3) is also low. As a result US women enter pregnancy with lower DHA status than other countries in the developed world suggesting a potential deficiency of an important nutrient that has been shown to reduce inflammation. The goal of this Phase III Clinical Trial (randomized, double-blind, and placebo-controlled) is to test the primary hypothesis that supplementing US women with 1000 mg of docosahexaenoic acid (DHA), 800 mg above the amount currently in many prenatal nutritional supplements (~200 mg) during the half of pregnancy can reduce early preterm birth (ePTB) (<34 wk. gestation). This was a favorable secondary outcomes of a US trial (RO1 HD047315, Clinical Trials.gov ID: NCT00266825) conducted at one of the proposed study sites on which the current proposal is modeled. Secondary outcomes include birth weight <1500g and pregnancy outcomes (preeclampsia, gestational diabetes, C-section delivery). We propose a Bayesian Adaptive Design with 90% power to detect the hypothesized outcomes with an estimated 938 subjects that allows the study to stop early if strong results (probability >0.995) are observed before the study is scheduled to end and places 60% of the participants on the better DHA dose. Conventional equal randomization with 90% power would require 1200 subjects, be longer, and place only 50% of the participants on the better DHA dose. The proposed study has the potential to determine if nutritional supplementation with DHA during pregnancy can reduce the incidence of ePTB, a serious public health problem with large societal and family costs. The randomization design has the potential to significantly expedite findings to the research community and clinical practice.

The current proposal does not change the original scope, aims or research design of our ongoing RCT (R01 HD083292; ClinicalTrials.gov ID: NCT02626299) which seeks to determine whether high versus low DHA intake during pregnancy can successfully reduce early preterm birth. Instead this proposal directs additional resources to evaluate community based participatory research strategies for the recruitment and retention of underrepresented minorities, specifically pregnant Hispanic women. We seek to 1) identify barriers pregnant Hispanic women face when accessing clinical care, 2) identify their perception of clinical research participation as it relates to the health of their pregnancy and unborn child and 3) increase enrollment and retention of Hispanic women in our clinical trial to achieve a nationally representative sampling. A newly formed interdisciplinary collaboration with a multilingual, culturally appropriate center with a successful track record of Hispanic community engagement will guide our efforts. Outcome data will include the number of Hispanic participants who enroll into and complete our clinical trial as well as descriptive methods to improve commitment of underrepresented minorities for future studies.

PROJECT SUMMARY ABSTRACT The current proposal does not change the original scope, aims or research design of our ongoing RCT (R01 HD083292; ClinicalTrials.gov ID: NCT02626299) which seeks to determine whether high versus low DHA intake during pregnancy can successfully reduce early preterm birth. Instead this proposal directs additional resources to evaluate micronutrient consumption before and during pregnancy from both dietary supplement and food sources. We also intend to explore differences in nutrient intake by race, ethnicity and sociodemographic factors. Outcome data will include the overall intake of nutrients from diet and supplements separately and together and the comparison of these intakes to Dietary Reference Intakes. An interdisciplinary team including a biochemist, statistician and several Registered Dietitians with more than 35 years' experience in diet analysis will guide our efforts. Importantly, results from this supplement will directly address the Office of Dietary Supplements' goal to build future research capacity for studying the role of dietary supplements in health and disease. Long term we intend to augment on our findings by studying the nutrient status of trial participants as it relates to their nutrient intake.