Omega-3 Fatty Acid Supplementation to Prevent Preterm Birth in High Risk Pregnancies

• ClinicalTrials.gov Identifier: NCT00135902
• Recruitment Status: Completed
• First Posted: August 26, 2005
• Last Update Posted: July 12, 2019
• Sponsor: The George Washington University Biostatistics Center
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Information provided by (Responsible Party): The George Washington University Biostatistics Center

Study Description

Brief Summary:

A recently completed trial of weekly injections of 17 alpha hydroxyprogesterone caproate (17P) found significant effectiveness for 17P in preventing recurrent preterm birth. However, the group who received 17P in this trial still had a high rate of preterm birth. Several reports have shown that dietary supplementation of fish oil, which is rich in Omega-3 fatty acids, reduces the risk of preterm birth. This trial tests whether adding the Omega-3 supplement to 17P therapy has the potential for further reducing the risk of preterm birth in women who have previously had a spontaneous preterm delivery. The trial will compare Omega-3 fatty acid with placebo in women receiving 17P therapy. The hypothesis being tested is: "Among women at high risk for preterm birth receiving weekly injections of 17P, the addition of Omega-3 nutritional supplement will further reduce the rate of preterm birth."

Condition or disease	Intervention/treatment	Phase
Preterm Birth	Drug: 17 alpha-Hydroxyprogesterone Caproate and Omega-3 supplement; Drug: 17 alpha-hydroxy progesterone caproate and Placebo supplement	Phase 3

Detailed Description:

Preterm birth is the leading cause of perinatal mortality and morbidity. In a recently completed trial of weekly injections of 17 alpha hydroxyprogesterone caproate (17P), the National Institute of Child Health and Human Development (NICHD) Maternal Fetal Medicine Units (MFMU) Network found the treatments significantly beneficial in the prevention of recurrent preterm birth. Other studies have shown that fish oil supplementation can reduce the risk for preterm birth. The purpose of this study is to determine whether Omega-3, a polyunsaturated fatty acid nutritional supplement, in addition to injections of 17P, further decreases the rate of preterm birth in women at risk.

This study is a randomized, double-masked clinical trial with two study arms: a daily supplement of Omega-3 capsules containing 800 mg of DHA and 1200 mg of EPA or a daily supplement of a matching placebo. All patients will also receive weekly injections of 17P. Eight hundred pregnant women with a history of previous preterm delivery will be recruited for this study. After successfully completing a compliance run-in, which can begin as early as 15 weeks gestation, patients will be randomized and begin treatment between 16 and 22 weeks gestation. They will remain on study drug until 36 week and 6 days or delivery, whichever occurs first. Blood will be drawn at randomization and at a monthly visit falling between 25-29 weeks of gestation to test for compliance, to analyze genetic polymorphisms and to determine whether Omega-3 affects the production of inflammatory cytokines.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 800 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: A Randomized Trial of Omega-3 Fatty Acid Supplementation to Prevent Preterm Birth in Pregnancies at High Risk
• Study Start Date: February 2005
• Actual Primary Completion Date: March 2007
• Actual Study Completion Date: March 2008

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: 17P plus Omega-3 Supplement; Weekly 17 alpa hydroxyprogesterone caproate (17p) injections plus Omega 3 supplements, 4 capsules per day for up to 5 weeks. Each capsule contained 200 mg of docosahexaenoic acid (DHA) and 300 mg of eicosapentaenoic acid (EPA).	Drug: 17 alpha-Hydroxyprogesterone Caproate and Omega-3 supplement; Participants receive a weekly progesterone injection (17 alpha hydroxyprogesterone caproate) up to 37 weeks gestation and take daily Omega-3 supplements.
Placebo Comparator: 17P plus Placebo Supplement; Weekly 17 alpa hydroxyprogesterone caproate (17p) injections plus placebo capsules, 4 capsules per day for up to 5 weeks	Drug: 17 alpha-hydroxy progesterone caproate and Placebo supplement; Participants receive a weekly progesterone injection (17P) up to 37 weeks gestation and take daily placebo supplements

Outcome Measures

Primary Outcome Measures :

1. Delivery before than 37 weeks gestation [ Time Frame: Up to 37 weeks gestation ]
   Delivery before 37 weeks including any miscarriages occurring after randomization

Secondary Outcome Measures :

1. Delivery before 35 weeks gestation [ Time Frame: Up to 35 weeks gestation ]
2. Delivery before 32 weeks gestation [ Time Frame: Up to 32 weeks gestation ]
3. Delivery after 40 weeks gestation [ Time Frame: 40 weeks gestation or greater ]
4. Pregnancy loss or neonatal death [ Time Frame: Randomization to hospital discharge (up to 25 weeks) ]
5. Gestational age at delivery [ Time Frame: Delivery ]
6. Birth weight less than 2,500 grams [ Time Frame: Birth ]
7. Birth weight less than 1,500 grams [ Time Frame: Birth ]
8. Birth size small for gestational age at less than 10th percentile [ Time Frame: Birth ]
9. Birth size large for gestational age at more than 90th percentile [ Time Frame: Birth ]
10. Admission to neonatal intensive care or intermediate care nursery [ Time Frame: Delivery through neonatal discharge (up to 2 weeks) ]
11. Neonatal retinopathy of prematurity [ Time Frame: Delivery through neonatal discharge (up to 2 weeks) ]
12. Intraventricular Hemorrhage at any grade [ Time Frame: Delivery through neonatal discharge (up to 2 weeks) ]
13. Intraventricular Hemorrhage Grade 3 or 4 [ Time Frame: Delivery through neonatal discharge (up to 2 weeks) ]
14. Neonatal patent ductus arteriosus [ Time Frame: Delivery through neonatal discharge (up to 2 weeks) ]
15. Neonatal necrotizing enterocolitis [ Time Frame: Delivery through neonatal discharge (up to 2 weeks) ]
16. Neonatal sepsis [ Time Frame: Delivery through neonatal discharge (up to 2 weeks) ]
17. Neonatal respiratory distress syndrome [ Time Frame: Delivery through neonatal discharge (up to 2 weeks) ]
18. Neonatal surfactant use [ Time Frame: Delivery through neonatal discharge (up to 2 weeks) ]
19. Neonatal bronchopulmonary dysplasia [ Time Frame: Delivery through neonatal discharge (up to 2 weeks) ]
20. Neonatal transient tacypnea [ Time Frame: Delivery through neonatal discharge (up to 2 weeks) ]
21. Neonatal supplemental oxygen support [ Time Frame: Delivery through neonatal discharge (up to 2 weeks) ]
22. Neonatal ventilator support [ Time Frame: Delivery through neonatal discharge (up to 2 weeks) ]

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Documented history of previous singleton spontaneous birth
• Singleton pregnancy
• Gestational age at randomization between 16 and 22 weeks

Exclusion Criteria:

• Major fetal anomaly or demise
• Regular intake of fish oil supplements
• Daily use of nonsteroidal anti-inflammatory agents
• Allergy to fish or fish products
• Gluten intolerant
• Heparin use or known thrombophilia
• Hemophilia
• Planned termination
• Current hypertension or current use of antihypertensive medications
• Type D, F or R diabetes
• Maternal medical complications
• Current or planned cerclage
• Illicit drug or alcohol abuse during current pregnancy
• Delivery at a non-Network hospital
• Participation in another pregnancy intervention study
• Participation in this trial in a previous pregnancy

Contacts and Locations

Locations

United States, Alabama

University of Alabama - Birmingham

Birmingham, Alabama, United States

United States, Illinois

Northwestern University

Chicago, Illinois, United States

United States, Michigan

Wayne State University

Detroit, Michigan, United States

United States, New York

Columbia University

New York, New York, United States

United States, North Carolina

University of North Carolina - Chapel Hill

Chapel Hill, North Carolina, United States

Wake Forest University School of Medicine

Winston-Salem, North Carolina, United States

United States, Ohio

Case Western University

Cleveland, Ohio, United States

Ohio State University

Columbus, Ohio, United States

United States, Pennsylvania

Drexel University

Philadelphia, Pennsylvania, United States

University of Pittsburgh Magee Womens Hospital

Pittsburgh, Pennsylvania, United States

United States, Rhode Island

Brown University

Providence, Rhode Island, United States

United States, Utah

University of Utah Medical Center

Salt Lake City, Utah, United States

Sponsors and Collaborators

The George Washington University Biostatistics Center

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Menachem Miodovnik, MD; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Principal Investigator: Elizabeth A Thom, PhD; George Washington University Biostatistics Center
• Principal Investigator: Margaret Harper, MD; Wake Forest University Health Sciences

More Information

Additional Information:

Related Info 

Publications of Results:

Harper M, Thom E, Klebanoff MA, Thorp J Jr, Sorokin Y, Varner MW, Wapner RJ, Caritis SN, Iams JD, Carpenter MW, Peaceman AM, Mercer BM, Sciscione A, Rouse DJ, Ramin SM, Anderson GD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Omega-3 fatty acid supplementation to prevent recurrent preterm birth: a randomized controlled trial. Obstet Gynecol. 2010 Feb;115(2 Pt 1):234-242. doi: 10.1097/AOG.0b013e3181cbd60e.

Other Publications:

Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, Spong CY, Hauth JC, Miodovnik M, Varner MW, Leveno KJ, Caritis SN, Iams JD, Wapner RJ, Conway D, O'Sullivan MJ, Carpenter M, Mercer B, Ramin SM, Thorp JM, Peaceman AM, Gabbe S; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003 Jun 12;348(24):2379-85. Erratum in: N Engl J Med. 2003 Sep 25;349(13):1299.

Olsen SF, Secher NJ, Björnsson S, Weber T, Atke A. The potential benefits of using fish oil in relation to preterm labor: the case for a randomized controlled trial? Acta Obstet Gynecol Scand. 2003 Nov;82(11):978-82. Review.

Duley L. Prophylactic fish oil in pregnancy. The Cochrane Pregnancy & Childbirth Database (Issue 2, 1995).

Olsen SF, Secher NJ, Tabor A, Weber T, Walker JJ, Gluud C. Randomised clinical trials of fish oil supplementation in high risk pregnancies. Fish Oil Trials In Pregnancy (FOTIP) Team. BJOG. 2000 Mar;107(3):382-95.

Olsen SF, Secher NJ. Low consumption of seafood in early pregnancy as a risk factor for preterm delivery: prospective cohort study. BMJ. 2002 Feb 23;324(7335):447.

Reece MS, McGregor JA, Allen KG, Harris MA. Maternal and perinatal long-chain fatty acids: possible roles in preterm birth. Am J Obstet Gynecol. 1997 Apr;176(4):907-14.

Dunstan JA, Mori TA, Barden A, Beilin LJ, Taylor AL, Holt PG, Prescott SL. Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomized, controlled trial. J Allergy Clin Immunol. 2003 Dec;112(6):1178-84.

Cadroy Y, Dupouy D, Boneu B. Arachidonic acid enhances the tissue factor expression of mononuclear cells by the cyclo-oxygenase-1 pathway: beneficial effect of n-3 fatty acids. J Immunol. 1998 Jun 15;160(12):6145-50.

Lee JY, Plakidas A, Lee WH, Heikkinen A, Chanmugam P, Bray G, Hwang DH. Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids. J Lipid Res. 2003 Mar;44(3):479-86. Epub 2002 Dec 1.

Calder PC. Dietary fatty acids and the immune system. Nutr Rev. 1998 Jan;56(1 Pt 2):S70-83. Review.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Harper M, Li L, Zhao Y, Klebanoff MA, Thorp JM Jr, Sorokin Y, Varner MW, Wapner RJ, Caritis SN, Iams JD, Carpenter MW, Peaceman AM, Mercer BM, Sciscione A, Rouse DJ, Ramin SM, Anderson GD; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network*. Change in mononuclear leukocyte responsiveness in midpregnancy and subsequent preterm birth. Obstet Gynecol. 2013 Apr;121(4):805-811. doi: 10.1097/AOG.0b013e3182878a80.

Klebanoff MA, Harper M, Lai Y, Thorp J Jr, Sorokin Y, Varner MW, Wapner RJ, Caritis SN, Iams JD, Carpenter MW, Peaceman AM, Mercer BM, Sciscione A, Rouse DJ, Ramin SM, Anderson GD; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units Network (MFMU). Fish consumption, erythrocyte fatty acids, and preterm birth. Obstet Gynecol. 2011 May;117(5):1071-1077. doi: 10.1097/AOG.0b013e31821645dc.

Harper M, Zheng SL, Thom E, Klebanoff MA, Thorp J Jr, Sorokin Y, Varner MW, Iams JD, Dinsmoor M, Mercer BM, Rouse DJ, Ramin SM, Anderson GD; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units Network (MFMU). Cytokine gene polymorphisms and length of gestation. Obstet Gynecol. 2011 Jan;117(1):125-130. doi: 10.1097/AOG.0b013e318202b2ef.

• Responsible Party: The George Washington University Biostatistics Center
• ClinicalTrials.gov Identifier: NCT00135902
• Other Study ID Numbers: HD36801-Omega-3; U10HD021410 ( U.S. NIH Grant/Contract ); U10HD027869 ( U.S. NIH Grant/Contract ); U10HD027917 ( U.S. NIH Grant/Contract ); U10HD027860 ( U.S. NIH Grant/Contract ); U10HD027915 ( U.S. NIH Grant/Contract ); U10HD034208 ( U.S. NIH Grant/Contract ); U10HD034136 ( U.S. NIH Grant/Contract ); U10HD040500 ( U.S. NIH Grant/Contract ); U10HD040485 ( U.S. NIH Grant/Contract ); U10HD040544 ( U.S. NIH Grant/Contract ); U10HD040545 ( U.S. NIH Grant/Contract ); U10HD040560 ( U.S. NIH Grant/Contract ); U10HD040512 ( U.S. NIH Grant/Contract ); U10HD036801 ( U.S. NIH Grant/Contract )
• First Posted: August 26, 2005
• Last Update Posted: July 12, 2019
• Last Verified: July 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The data will be shared after completion and publication of the main analyses in accordance with NIH policy. The contact to obtain datasets is mfmudatasets@bsc.gwu.edu.

Keywords provided by The George Washington University Biostatistics Center:

Preterm birth; Progesterone; Omega-3 fatty acid; Pregnancy

Additional relevant MeSH terms:

Premature Birth; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Progesterone; 17 alpha-Hydroxyprogesterone Caproate; 11-hydroxyprogesterone; Progestins; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Estrogen Antagonists; Hormone Antagonists