Docosahexaenoic Acid (DHA) Supplementation in High Risk Pregnancies

Inflammation Clinical Trial

Official title:

Placebo Controlled Trial of Docosahexaenoic Acid (DHA) Supplementation in High Risk Pregnancies

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04069195
• Other study ID #: WRNMMC-2018-0126
• Status: Recruiting
• Phase: N/A
• Start date: February 1, 2019
• Est. completion date: December 1, 2020

Study information

• Verified date: August 2019
• Source: Walter Reed National Military Medical Center
• Contact: Peter F Knickerbocker, DO
• Phone: 215-298-2476
• Email: peteknickerbocker[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Purpose: Determine the effects of maternal docosahexaenoic acid (DHA) supplementation during pregnancy on levels of DHA, synaptamide (novel anti-inflammatory metabolite), and inflammatory biomarkers during pregnancy and at delivery

Research Design: Double blind randomized placebo-controlled study of maternal DHA supplementation during pregnancy.

Methodology /Technical Approach: Investigators plan to enroll 100 pregnant women with a high risk pregnancy related to (1) a pre-pregnancy Body Mass Index (BMI) of ≥30.0 kg/m2 and/or (2) a history of prior preterm delivery at ≤35+6 weeks gestation. Women will be enrolled between the 8th and 14th week of pregnancy and randomized to receive a once daily DHA supplement (DSM Nutritional Products, Columbia Maryland, DHA capsule 441mg/cap) or a placebo (DSM Nutritional Products, Columbia Maryland, Corn Oil/Soybean oil 50/50 mix) for the duration of the pregnancy. DHA is an omega-3 long chain polyunsaturated fatty acid (LCPUFA) and placebo composed of omega-6 LCPUFA's. Investigators will measure maternal levels of plasma DHA, Synaptamide and inflammatory biomarkers at enrollment, at 26-30 weeks of pregnancy, and from cord blood at delivery. Sociodemographic and clinical characteristics will be collected for each mother from pregnancy onset until discharge following delivery. The infant health record and parental report will be reviewed to record clinical data from birth to 12 months corrected age for short term health outcomes potentially related to inflammation-related morbidities, including growth and development, acute infection requiring hospital admission, and any allergic disorder. All plasma samples will be processed at Dr. Kim's NIAAA/NIH laboratories using high-performance liquid chromatography with tandem mass spectrometry

Description:

All pregnant women meeting the inclusion/exclusion criteria will be identified at the time of their regular OB appointments between the 8th and the 14th week of pregnancy (+/- 3 days) Research team members will approach potential subjects to explain the study and obtain consent for their participation Patients who give their consent for enrollment will be asked to complete a dietary survey at the time of enrollment Patients will be given a paper script for study drug to be taken to the Walter Reed Military Medical Center pharmacy to obtain study drug The Investigational Pharmacy will randomize the patients in double blinded fashion to the intervention group or placebo group.

Patients in the intervention group will recieve a ~1000mg capsule containing ~400mg of DHA. This is not standard of care and is being done for research purposes only Patients in the Placebo group will recieve a ~1000mg capusle containing no DHA and filled with 50:50 mix of corn and soybean oils. This oil is ubiquitous in the american diet and only a very small amount of additional oil will be ingested for study purposes. Giving pregnant women this oil is not standard of care and is being done for research purposes only The placebo and intervention drugs will be packaged in the same capsule membrane and will be indistinguishable by color, shape, or taste.

Patients will be instructed to take 1 capule PO daily until their child is delivered Patients will be issued a 3 month supply of study drug at enrollment and will get refills from the investigational pharmacy

≤5ml of whole blood will be obtained from each subject at enrollment and at 26-30 weeks gestation (+/- 3 days), as part of a routine blood sampling. It is standard of care to collect blood at this point in pregnancy for lab evaluation. The additional tube of blood collected for this study is for research purposes only and not part of the standard of care. This sample will be centrifuged, and the separated plasma will be labeled and frozen at -80° C pending transport to Dr. Kim's lab at the National Institute on Alcohol Abuse and Alcoholism (NIAAA) for bulk analyses.

At delivery, ≤5ml of umbilical cord blood will be obtained from an umbilical artery and from the umbilical vein. These samples will be processed and stored in a similar fashion as the earlier samples. Cord blood is a medical waste product, and collection will therefore have no adverse effect for either mother or newborn. It is standard of care to collect cord blood by OB request for lab evaluation. Collecting additional cord blood for this study anaylsis is for research purposes only All enrollees will complete a dietary survey upon enrollment at 8-14 weeks (+/- 3 days), at 26-30th week of pregnancy (+/- 3 days), and during the delivery admission. This survey will also include the subject's self-report on compliance with taking the study supplement All plasma samples collected will be processed at Dr. Kim's National Institute on Alcohol Abuse and Alcoholism/ National Insititute of Health (NIAAA/NIH) laboratories The Cytokine Assays for IL-6, Il-10, TNF- alpha will be run in Dr Kim's lab using Ensyme Linked Immunosorbent Assay (ELISA) testing The DHA and Synaptamide levels will be analyzed in Dr. Kim's lab using High performance liquid chromatrography with tandem mass spectrometry All babies from multiple birth pregnancies will be enrolled in this study The offspring of enrolled women will be followed through 12 months corrected age to assess the longer term outcomes of study intervention Information will be collected from the maternal medical record at time of enrollment, infant delivery and postpartum discharge.

Information will be collected from the infant medical record at time of birth discharge, and 12 months corrected age.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 210
• Est. completion date: December 1, 2020
• Est. primary completion date: December 1, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• regnant female military health care beneficiaries =18 years of age

• Between the 8th and 14th week of pregnancy at enrollment

• BMI of =30.0 kg/m2 and/or history of previous preterm delivery at <36 weeks gestation

• Planning to deliver at WRNMMC

• DEERS-eligible

• All infants born to mothers enrolled in this study who do not meet any exclusion criteria

Exclusion Criteria:

• Routine use of DHA supplement (including DHA containing prenatal vitamins) and/or fish consumption greater than twice per week

• Women with a fish allergy

• Known major fetal anomaly believed to be lethal

• Maternal treatment for clotting disorder

• Allergy to corn or soybean oils

Related Conditions & MeSH terms

• Inflammation
• Pregnancy Related

Intervention

Dietary Supplement:
• DHA supplement
Patient's will be randomized to recieve either DHA or 50:50 corn oil/soybean oil supplement as a once daily supplement to be taken from enrollment through delivery of their infant
• Corn Oil: Soybean Oil
Patient's will be randomized to recieve either DHA or 50:50 corn oil/soybean oil supplement as a once daily supplement to be taken from enrollment through

Locations

Country	Name	City	State
United States	Walter Reed National Miltiary medical center	Bethesda	Maryland

Sponsors (4)

Lead Sponsor	Collaborator
Walter Reed National Military Medical Center	DSM Nutritional Products, Inc., National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

References & Publications (11)

Balvers MG, Verhoeckx KC, Plastina P, Wortelboer HM, Meijerink J, Witkamp RF. Docosahexaenoic acid and eicosapentaenoic acid are converted by 3T3-L1 adipocytes to N-acyl ethanolamines with anti-inflammatory properties. Biochim Biophys Acta. 2010 Oct;1801(10):1107-14. doi: 10.1016/j.bbalip.2010.06.006. Epub 2010 Jun 27. — View Citation

Cheng SB, Sharma S. Interleukin-10: a pleiotropic regulator in pregnancy. Am J Reprod Immunol. 2015 Jun;73(6):487-500. doi: 10.1111/aji.12329. Epub 2014 Oct 1. Review. — View Citation

De Dooy JJ, Mahieu LM, Van Bever HP. The role of inflammation in the development of chronic lung disease in neonates. Eur J Pediatr. 2001 Aug;160(8):457-63. Review. — View Citation

Dunstan JA, Simmer K, Dixon G, Prescott SL. Cognitive assessment of children at age 2(1/2) years after maternal fish oil supplementation in pregnancy: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2008 Jan;93(1):F45-50. Epub 2006 Dec 21. — View Citation

Hofer N, Kothari R, Morris N, Müller W, Resch B. The fetal inflammatory response syndrome is a risk factor for morbidity in preterm neonates. Am J Obstet Gynecol. 2013 Dec;209(6):542.e1-542.e11. doi: 10.1016/j.ajog.2013.08.030. Epub 2013 Aug 29. — View Citation

Kim HY, Spector AA. Synaptamide, endocannabinoid-like derivative of docosahexaenoic acid with cannabinoid-independent function. Prostaglandins Leukot Essent Fatty Acids. 2013 Jan;88(1):121-5. doi: 10.1016/j.plefa.2012.08.002. Epub 2012 Sep 5. Review. — View Citation

Ma L, Li N, Liu X, Shaw L, Li Calzi S, Grant MB, Neu J. Arginyl-glutamine dipeptide or docosahexaenoic acid attenuate hyperoxia-induced lung injury in neonatal mice. Nutrition. 2012 Nov-Dec;28(11-12):1186-91. doi: 10.1016/j.nut.2012.04.001. — View Citation

Makrides M, Gibson RA, McPhee AJ, Yelland L, Quinlivan J, Ryan P; DOMInO Investigative Team. Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children: a randomized controlled trial. JAMA. 2010 Oct 20;304(15):1675-83. doi: 10.1001/jama.2010.1507. — View Citation

Martin CR, Dasilva DA, Cluette-Brown JE, Dimonda C, Hamill A, Bhutta AQ, Coronel E, Wilschanski M, Stephens AJ, Driscoll DF, Bistrian BR, Ware JH, Zaman MM, Freedman SD. Decreased postnatal docosahexaenoic and arachidonic acid blood levels in premature infants are associated with neonatal morbidities. J Pediatr. 2011 Nov;159(5):743-749.e1-2. doi: 10.1016/j.jpeds.2011.04.039. Epub 2011 Jun 12. — View Citation

Meijerink J, Poland M, Balvers MG, Plastina P, Lute C, Dwarkasing J, van Norren K, Witkamp RF. Inhibition of COX-2-mediated eicosanoid production plays a major role in the anti-inflammatory effects of the endocannabinoid N-docosahexaenoylethanolamine (DHEA) in macrophages. Br J Pharmacol. 2015 Jan;172(1):24-37. doi: 10.1111/bph.12747. Epub 2014 Sep 23. — View Citation

Valentine CJ. Maternal dietary DHA supplementation to improve inflammatory outcomes in the preterm infant. Adv Nutr. 2012 May 1;3(3):370-6. doi: 10.3945/an.111.001248. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Measure DHA	Measurement of maternal plasma DHA using tandem mass spec	Sample obtained between 8-14 weeks of pregnancy
Primary	Measure DHA	Measurement of maternal plasma DHA using tandem mass spec	Sample obtained between 26-30 weeks of pregnancy
Primary	Measure DHA	Measurement of fetal plasma DHA using tandem mass spec	Sample obtained from cord blood at time of infant delivery
Primary	Measure synaptamide	Measurement of maternal plasma synaptamide using tandem mass spec	Sample obtained between 8-14 weeks of pregnancy
Primary	Measure synaptamide	Measurement of maternal plasma synaptamide using tandem mass spec	Sample obtained between 26-30 weeks of pregnancy
Primary	Measure synaptamide	Measurement of fetal plasma synaptamide using tandem mass spec	Sample obtained from cord blood at time of infant delivery
Primary	Measure inflammatory biomarkers	Measurement of plasma cytokine levels using ELISA human cytokine panel	Sample obtained between 8-14 weeks of pregnancy
Primary	Measure inflammatory biomarkers	Measurement of plasma cytokine levels using ELISA human cytokine panel	Sample obtained between 26-30 weeks of pregnancy
Primary	Measure inflammatory biomarkers	Measurement of plasma cytokine levels using ELISA human cytokine panel	Sample obtained from cord blood at time of infant delivery
Secondary	Maternal Gestational weight gain at end of pregnancy in placebo vs. DHA supplement groups	Compare maternal gestational weight gain at the end of pregnancy between intervention and placebo groups	At time of infant delivery
Secondary	Infant delivery method	Compare delivery method used to delivery infant between intervention and placebo groups	At time of infant delivery
Secondary	Delivery complications	Compare any documented delivery complications between intervention and placebo groups	at time of infant delivery
Secondary	Maternal death	Number of maternal deaths in intervention group vs placebo group	From enrollment in study at 8-14 weeks of pregnancy until 6 months after infant delivery
Secondary	Pre-eclampsia	Presence or absence of pre-eclampsia in intervention vs placebo groups	From enrollment in study at 8-14 weeks of pregnancy until 42 weeks of pregnancy or day of infant delivery, whichever happens first
Secondary	chorioamionitis	Presence or absence of chorioamionitis in intervention vs placebo groups	From enrollment in study at 8-14 weeks of pregnancy until 42 weeks of pregnancy or day of infant delivery, whichever happens first
Secondary	Gestational Diabetes Melitus	Presence or absence of Gestational Diabetes Mellitus in intervention vs placebo groups	From enrollment in study at 8-14 weeks of pregnancy until 42 weeks of pregnancy or day of infant delivery, whichever happens first
Secondary	non-gestational Diabetes mellitus	Presence or absence of non-Gestational Diabetes Mellitus in intervention vs placebo groups	From enrollment in study at 8-14 weeks of pregnancy until 42 weeks of pregnancy or day of infant delivery, whichever happens first
Secondary	Preterm Premature Rupture of Membranes	Presence or absence of Preterm Premature Rupture of Membranes in intervention vs placebo groups	From enrollment in study at 8-14 weeks of pregnancy until 42 weeks of pregnancy or day of infant delivery, whichever happens first
Secondary	going past due dates	Presence or absence of going past due dates in intervention vs placebo groups	during last month of pregnancy
Secondary	Placental pathology	Any placental pathology documented on maternal delivery summary in intervention vs. placebo groups	at time of delivery
Secondary	Head circumference at birth	Measurement of head circumference at birth in placebo vs. Intervention	At time of infant birth
Secondary	Length at birth	Measurement of length at birth in placebo vs. Intervention	At time of infant birth
Secondary	weight at birth	Measurement of weight at birth in placebo vs. Intervention	At time of infant birth
Secondary	Gestational age at birth	Gestational age at infant birth in both placebo and intervention groups	At time of infant birth
Secondary	APGAR score at 1 min	APGAR score assessed for infants in both placebo and intervention groups	At time of infant birth
Secondary	APGAR score at 5 min	APGAR score assessed for infants in both placebo and intervention groups	At time of infant birth
Secondary	Resuscitation beyond warm/dry stimulate at birth	Presence or absence of any resuscitation beyond warm, dry and stimulate at infant birth	At time of infant birth
Secondary	Presence or absence or requirement for respiratory assistance within the first 24 hours after birth	Presence or absence of any respiratory support outside of the delivery room in first 24 hours of birth placebo vs intervention groups	From NICU admission to 24 hours after birth
Secondary	Days of antibiotic exposure during birth hospitalization	Number of 24hr periods in which infant was exposed to antibiotics during birth hospitalization	During birth admission up to 8 months of chronologic age or discharge from hospital whichever happens sooner
Secondary	NICU admission	Presence or absence of NICU admission in placebo vs intervention groups	Within the first 5 days of infant's life
Secondary	Duration of birth admission	Number of 24hr periods patient was present in hospital during birth admission	Birth through 12 months of age or infant discharge, whichever occurs sooner
Secondary	Requirement for phototherapy during birth admission	Presence or absence of phototherapy during birth admission in placebo vs intervention groups	Birth through 14 days of infant life
Secondary	Culture proven sepsis	Presence or absence of culture proven sepsis during birth admission in placebo vs intervention groups	From birth through 12 months or until infant discharge whichever occurs sooner
Secondary	Infant Death	Number of infants that died during birth hospitalization in both the placebo and intervention groups	From birth through 12 months or until infant discharge whichever occurs sooner
Secondary	Weight at infant hospital discharge	Weight at infant hospital discharge in placebo vs intervention group	At time of infant's first discharge from hospital or at 12 months corrected, whichever comes first
Secondary	head circumference at infant hospital discharge	head circumference at infant hospital discharge in placebo vs intervention group	At time of infant's first discharge from hospital or at 12 months corrected, whichever comes first
Secondary	Length at infant hospital discharge	Length at infant hospital discharge in placebo vs intervention group	At time of infant's first discharge from hospital or at 12 months corrected, whichever comes first
Secondary	Feeding plan at infant discharge	Feeding plan documented as exclusive breastfeeding, formula and breastfeeding or exclusive formula feeding	At 12 months chronological if still admitted or at infant discharge, whichever occurs sooner
Secondary	Infant diagnosis in medical record	Compare infant diagnosis recorded in medical record in placebo vs intervention group	at 12 months corrected
Secondary	infant weight at 6 months corrected age	Weight at 6 months corrected age documented in medical record in placebo vs intervention group	at 6 months corrected
Secondary	infant weight at 12 months corrected age	Weight at 12 months corrected age documented in medical record in placebo vs intervention group	at 12 months corrected
Secondary	head circumferene weight at 6 months corrected age	head circumferene at 6 months corrected age documented in medical record in placebo vs intervention group	at 6 months corrected
Secondary	head circumference weight at 12 months corrected age	head circumference at 12 months corrected age documented in medical record in placebo vs intervention group	at 12 months corrected
Secondary	Length weight at 6 months corrected age	Length at 6 months corrected age documented in medical record in placebo vs intervention group	at 6 months corrected
Secondary	Length weight at 12 months corrected age	Length at 12 months corrected age documented in medical record in placebo vs intervention group	at 12 months corrected
Secondary	Number of outpatient visits for infant during first 12 months corrected	Number of outpatient visits recorded during first 12 months corrected in placebo vs. intervention groups	birth through12 months corrected
Secondary	Failure to thrive in for infant	Presence or absence of diagnosis "failure to thrive" in medical record through first 12 months corrected in placebo vs intervention	birth through 12 months corrected
Secondary	number of inpatient days for infant through 12 months corrected	number of inpatient days for infant through 12 months corrected in intervention vs placebo	birth through 12 months corrected
Secondary	Indication of infant developmental delay in medical record from birth through 12 months corrected	Presence or absence of any indication of developmental delay recorded by physician in the medical record through 12 months corrected in intervention vs placebo groups	birth through 12 months corrected
Secondary	Number of antibiotic prescriptions for infant through first 12 months corrected	Number of antibiotic prescriptions for infant through first 12 months corrected in intervention vs placebo	birth through 12 months corrected
Secondary	Documented infant feeding plan through first year	Documented infant feeding plan through first year. Exclusive breastfeeding, formula and breastfeeding or exclusive formula	birth through 12 months corrected