Clinical trial NCT02336243: A Randomized Trial of Docosahexaenoic Acid Supplementation During Pregnancy to Prevent Deep Placentation Disorders
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Premature Birth
Preeclampsia
Fetal Growth Retardation
Stillbirth
Keywords: docosahexaenoic acid
premature birth
placentation disorders
preeclampsia
fetal growth
Lead sponsor: Pontificia Universidad Catolica de Chile
Sponsor class: OTHER
Collaborators: name: University of Chile
name: Laboratorio Gynopharm - CFR
First posted: 2015-01-12
Enrollment: 2400
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: 34 weeks of pregnancy
Secondary outcomes:
measure: Stillbirth
timeFrame: During pregnancy
measure: Intrauterine growth restriction
timeFrame: At delivery
measure: Severe intrauterine growth restriction
timeFrame: At birth
measure: Preterm birth
timeFrame: At birth
measure: Perinatal death
timeFrame: From the 20th gestational week to the 28th day of life
measure: Neonatal
timeFrame: From birth to the 28th day of life
measure: Respiratory Distress Syndrome (RDS)
timeFrame: Until the 28th day of life
measure: Bronchopulmonary Dysplasia (BPD)
timeFrame: Until the 28th day of life
measure: Intraventricular Hemorrhage (IVH)
timeFrame: Until the 28th day of life
measure: Proven Early onset Sepsis
timeFrame: Within the first 48 hours of life
measure: Necrotizing Enterocolitis
timeFrame: Until the 28th day of life
measure: Low birth weight
timeFrame: At birth
measure: Admitted to Neonatal Intensive Care Unit (NICU)
timeFrame: Until the 28th day of life
measure: Birth biometry
timeFrame: At birth
measure: Cesarean section
timeFrame: At delivery
measure: Preeclampsia
timeFrame: From pregnancy to discharge after delivery
measure: Gestational Diabetes (GDM)
timeFrame: During pregnancy
measure: Premature rupture of membranes
timeFrame: During pregnancy
measure: Maternal Venous Thrombosis
timeFrame: During pregnancy
measure: Bleeding during pregnancy
timeFrame: During pregnancy
measure: Placental Abruptio
timeFrame: During pregnancy
measure: Postpartum bleeding
timeFrame: Postpartum period
measure: Postpartum depression
timeFrame: At the 6th postpartum week
Other outcomes:
Locations:
city: Santiago
country: Chile
facility: Centro de Salud Familiar ANCORA Juan Pablo II
city: Santiago
country: Chile
facility: Centro de Salud Familiar ANCORA Madre Teresa de Calcuta
city: Santiago
country: Chile
facility: Centro de Salud Familiar ANCORA San Alberto Hurtado
city: Santiago
country: Chile
facility: Centro Medico Lira 85
city: Santiago
country: Chile
facility: Centro Medico San Joaquin
Study officials:
affiliation: Pontificia Universidad Catolica de Chile
name: Jorge Carvajal, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Pontificia Universidad Catolica de Chile
name: Claudio Vera, MSc
role: STUDY_DIRECTOR
affiliation: Pontificia Universidad Catolica de Chile
name: Paulina Rojas, MD
role: STUDY_DIRECTOR
affiliation: Pontificia Universidad Catolica de Chile
name: Paola Casanello, PhD
role: STUDY_DIRECTOR
affiliation: University of Chile
name: Mauro Parra, MD
role: STUDY_DIRECTOR
affiliation: Pontificia Universidad Catolica de Chile
name: Christian Figueroa, MD
role: STUDY_DIRECTOR
affiliation: Pontificia Universidad Catolica de Chile
name: Sergio González, MD
role: STUDY_DIRECTOR
References: