A Randomized Trial of Docosahexaenoic Acid Supplementation During Pregnancy to Prevent Deep Placentation Disorders

Premature Birth Clinical Trial

Official title:

Docosahexaenoic Acid (DHA) Supplementation During Pregnancy to Prevent Deep Placentation Disorders: A Randomized Clinical Trial and a Study of the Molecular Pathways of Abnormal Placentation Prevention

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02336243
• Other study ID #: 13-217
• Secondary ID: 1141207
• Status: Recruiting
• Phase: Phase 3
• First received: October 19, 2014
• Last updated: November 3, 2015
• Start date: May 2015
• Est. completion date: April 2018

Study information

• Verified date: November 2015
• Source: Pontificia Universidad Catolica de Chile
• Contact: Jorge Carvajal, PhD
• Phone: +56 223543409
• Email: jcarva[@]med.puc.cl
• Is FDA regulated: No
• Health authority: Chile: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

This study evaluates the effectiveness of maternal supplementation with Docosahexaenoic acid (DHA) early in pregnancy to reduce the incidence of deep placentation disorders: preterm birth, preterm labor, preterm premature rupture of membranes, preeclampsia and fetal growth restriction. Half of the participants in early pregnancy will receive DHA 600 mg per day, while the other half will receive placebo. Investigators will study also the ability of DHA supplementation, early in pregnancy, to enhance invasion and transformation of spiral arteries by trophoblast, as deep placentation indicators.

Description:

Introduction: uteroplacental ischemia may cause preterm birth, either due to preterm labor, preterm premature rupture of membranes, or medical indication (in the presence of preeclampsia or fetal growth restriction). Uteroplacental ischemia is the product of defective deep placentation, that is a failure of invasion and transformation of the spiral arteries by the trophoblast. It has been reported that the failure of normal placentation generates a series of clinical abnormalities nowadays called "deep placentation disorders"; they include preeclampsia (PE), fetal growth restriction (FGR), preterm labor (PL), preterm premature rupture of membranes (PPROM), in utero fetal death and placental abruption. Strategies to prevent deep placentation disorders have been just partially effective. Docosahexaenoic acid (DHA) is an essential fatty acid of the family of long chain polyunsaturated fatty acids (LC-PUFAs) or omega-3 fatty acids. Early reports, suggested that a LC-PUFAs rich diet reduces the incidence of deep placentation disorders. Recent randomized controlled trials are inconsistent to show the benefit of DHA supplementation during pregnancy to prevent deep placentation disorders; but most of them showed that DHA supplementation was associated to lower risk of early preterm birth.

Hypothesis: investigators propose that Docosahexaenoic acid (DHA) supplementation, early in pregnancy, reduces the incidence of deep placentation disorders (preterm birth, preterm labor, preterm premature rupture of membranes, preeclampsia and fetal growth restriction), by improving deep placentation physiology: invasion and transformation of spiral arteries by trophoblast.

General Goals: in this proposal investigators aimed to

1. Assess the effectiveness of maternal supplementation with Docosahexaenoic acid (DHA) early in pregnancy to reduce the incidence of deep placentation disorders: preterm birth, preterm labor, preterm premature rupture of membranes, preeclampsia and fetal growth restriction.

2. Study the ability of DHA supplementation, early in pregnancy, to enhance invasion and transformation of spiral arteries by trophoblast, as deep placentation indicators. Methodology: investigators will conduct a randomized, placebo controlled, double blind, clinical trial of maternal supplementation with DHA (Docosahexaenoic acid) to prevent deep placentation disorders. Women will be recruited before 16 weeks of pregnancy from 5 ambulatory centers, 2.400 pregnant women will be assigned to 600 mg DHA per day or placebo. A composite outcome will be the primary outcome of the study. The components of the composite outcome will be: preterm birth < 34+0 weeks gestation; early preeclampsia (<34+0 weeks) and severe fetal growth restriction (lower than the 2 percentile and < 34+0 weeks). Each of the outcomes of the composite outcome and other clinically relevant maternal and fetal outcomes will be evaluated as the secondary outcomes of the study. Clinical samples will be obtained from pregnant women on both groups, including: plasma, trophoblast, placental bed and myometrium, to study changes of deep placentation or defective placentation markers. Trophoblast cell lines will be used to study the effect of DHA on trophoblast function in vitro.

Expected outcome: In the randomized clinical trial, a 50% reduction in the incidence of the composite outcome in the DHA group (4% placebo vs. 2% DHA) is expected. Investigators expect to decrease defective deep placentation (placental bed biopsies) and defective placentation markers in DHA supplemented women. Investigators expect also to demonstrate that DHA enhances trophoblast migration and invasion in vitro and decreases production of inflammatory cytokines and anti-vasculogenic mediators.

Relevance: if the findings are positive, DHA supplementation, early in pregnancy, will become a safe and effective strategy for primary prevention of highly relevant pregnancy diseases, such as preterm birth, preeclampsia and fetal growth restriction.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 2400
• Est. completion date: April 2018
• Est. primary completion date: March 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

• Women 18 years old or older at time of consent

• Capability of the subject to comprehend and comply with study requirements

• Live embryo or fetus (documented with positive fetal heart rate prior randomisation)

• Gestational age before 16+0 weeks of pregnancy

• Planning to deliver at Hospital Dr. Sótero del Río, Hospital Padre Hurtado, or Hospital Clínico Universidad Católica de Chile.

Exclusion Criteria:

• Preexisting diabetes mellitus.

• Uterine anatomic malformation (bicornuate, septate uterus).

• Already taking a prenatal supplement with DHA.

• Bleeding disorder in which DHA was contraindicated.

• Anticoagulant therapy.

• Documented history of drug or alcohol abuse.

• Embryo or Fetus with a known mayor abnormality.

• Unable to give written informed consent.

• In the judgment of the investigator, will be unwilling or unable to comply with study protocol.

• Currently participating in another fatty acid trial

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Fetal Growth Retardation
• Pre-Eclampsia
• Preeclampsia
• Premature Birth
• Stillbirth

Intervention

Dietary Supplement:
• Docosahexaenoic acid (DHA)
Docosahexaenoic acid (DHA), 600 mg per day. Each woman will take three DHA capsules per day (200 mg each), as early in gestation as possible and until the end of pregnancy.
• Placebo (for Docosahexaenoic acid (DHA))
Each women allocated to the placebo group, will receive three placebo capsules per day. The placebo capsules will have same size, aspect and flavor than the DHA capsules.

Locations

Country	Name	City	State
Chile	Centro de Salud Familiar ANCORA Juan Pablo II	Santiago
Chile	Centro de Salud Familiar ANCORA Madre Teresa de Calcuta	Santiago
Chile	Centro de Salud Familiar ANCORA San Alberto Hurtado	Santiago
Chile	Centro Medico Lira 85	Santiago
Chile	Centro Medico San Joaquin	Santiago

Sponsors (3)

Lead Sponsor	Collaborator
Pontificia Universidad Catolica de Chile	Laboratorio Gynopharm - CFR, University of Chile

Country where clinical trial is conducted

Chile, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite outcome: Preterm birth less than 34+0 gestational weeks or preeclampsia before 34+0 gestational weeks or severe fetal growth restrictions early than 34+0 gestational weeks.	Gestational age (first day of the last menstrual period (LMP) or estimated by ultrasound performed before 12+6 weeks of pregnancy).; Severe growth restriction defined as birth weight less than the 2nd percentile of population (according to the current national recommended standard).; Preeclampsia defined as blood pressure of 140 mm Hg systolic or higher or 90 mm Hg diastolic or higher that occurs after 20 weeks of pregnancy in a woman with previously normal blood pressure and proteinuria (urinary excretion of 0.3 g protein or higher in a 24-hour urine specimen). Or HELLP syndrome (Haemolysis, Elevated, Liver Enzymes, Low Platelets) or superimposed pre-eclampsia, defined as history of pre-existing hypertension (diagnosed pre-pregnancy or before 20+0 weeks' gestation) with new proteinuria. Or Eclampsia, defined as seizures that cannot be attributable to other causes, in a woman with preeclampsia.	34 weeks of pregnancy	No
Secondary	Stillbirth	Defined as death of the fetus of at least 500 grams birth weight or, if birth weight is unavailable, a gestational age of at least 20+0 weeks of gestation.	During pregnancy	No
Secondary	Intrauterine growth restriction	Birth weight less than the 10th percentile of the population standard for the gestational age.	At delivery	No
Secondary	Severe intrauterine growth restriction	birth weight less than the 2nd percentile of population (according to the current national recommended standard).	At birth	No
Secondary	Preterm birth	Birth < week 37th, < week 32th, < week 28th	At birth	No
Secondary	Perinatal death	number of deaths (fetal deaths and neonatal deaths) of babies =500 grams, if birth weight is unavailable, a gestational age =20+0 weeks, up to 28 completed days after birth.	From the 20th gestational week to the 28th day of life	No
Secondary	Neonatal	Death of a baby that occurred during the first 28 days of life	From birth to the 28th day of life	No
Secondary	Respiratory Distress Syndrome (RDS)	Defined as requiring assisted ventilation via endotracheal tube or CPAP (Continuous positive airway pressure) or supplemental oxygen greater or equal to 40% all within the first 24 hours of life and for a duration of greater than or equal to 24 hours, and either an x-ray compatible with RDS or surfactant given between the first 2 and 24 hours of life.	Until the 28th day of life	No
Secondary	Bronchopulmonary Dysplasia (BPD)	Defined as requiring oxygen supplementation at 28 days postnatal age	Until the 28th day of life	No
Secondary	Intraventricular Hemorrhage (IVH)	Diagnosed by imaging, categorized by: Grade 1: blood in germinal matrix; Grade 2: blood in germinal matrix and extending into ventricles; Grade 3: ventricular enlargement; Grade 4: intraparenchymal lesion	Until the 28th day of life	No
Secondary	Proven Early onset Sepsis	Within first 48hr of life, confirmed by positive blood or cerebrospinal fluid cultures	Within the first 48 hours of life	No
Secondary	Necrotizing Enterocolitis	Defined as Bell's stage II (definite case of necrotizing enterocolitis) or greater, or perforation of intestine identified by surgery, or at autopsy. (Neu J. Necrotizing enterocolitis: the search for a unifying pathogenic theory leading to prevention. Pediatr Clin North Am 1996; 43(2): 409-32.)	Until the 28th day of life	No
Secondary	Low birth weight	Number of Infants with a birth weight < 1500 grams, number of Infants with a birth weight < 2500 grams	At birth	No
Secondary	Admitted to Neonatal Intensive Care Unit (NICU)		Until the 28th day of life	No
Secondary	Birth biometry	Measurement of ponderal index (birth weight/height^3×100), head circumference (cm), Birth weight (grams).	At birth	No
Secondary	Cesarean section	Number of deliveries by cesarean section	At delivery	No
Secondary	Preeclampsia	Defined as blood pressure of 140 mm Hg systolic or higher or 90 mm Hg diastolic or higher that occurs after 20 weeks of pregnancy in a woman with previously normal blood pressure and proteinuria, defined as urinary excretion of 0.3 g protein or higher in a 24-hour urine specimen. Or HELLP (Haemolysis, Elevated, Liver Enzymes, Low Platelets) syndrome Or Superimposed pre-eclampsia, defined as history of pre-existing hypertension (diagnosed pre- pregnancy or before 20+0 weeks' gestation) with new proteinuria. Or Eclampsia, defined as seizures that cannot be attributable to other causes, in a woman with preeclampsia.	From pregnancy to discharge after delivery	No
Secondary	Gestational Diabetes (GDM)	Screening during pregnancy	During pregnancy	No
Secondary	Premature rupture of membranes	Rupture of the amniotic sac before the onset of labor	During pregnancy	No
Secondary	Maternal Venous Thrombosis	Venous Thrombosis confirmed by imaging during pregnancy	During pregnancy	Yes
Secondary	Bleeding during pregnancy	Genital bleeding diagnosed during pregnancy	During pregnancy	No
Secondary	Placental Abruptio	Prematurely detachment of a normal positioned placenta for the wall of uterus	During pregnancy	No
Secondary	Postpartum bleeding	Estimated bleeding more than 500 ml after vaginal birth or 1000 ml after cesarean section	Postpartum period	No
Secondary	Postpartum depression	Postpartum Depression defined by the Edinburgh Postnatal Depression Scale (EPDS)	At the 6th postpartum week	No