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

Phase 3

• Conditions: Preeclampsia; Fetal Growth Retardation; Premature Birth; Stillbirth
• Interventions: Dietary Supplement: Docosahexaenoic acid (DHA); Dietary Supplement: Placebo (for Docosahexaenoic acid (DHA))

• Registration Number: NCT02336243
• Lead Sponsor: Pontificia Universidad Catolica de Chile

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.

Study Timeline

• Study First Submitted: 2014-10-19
• Study First Submitted QC: 2015-01-07
• Study First Posted: 2015-01-12
• Study Start: 2015-05
• Status Verified: 2015-11
• Last Update Submitted: 2015-11-03
• Last Update Posted: 2015-11-04
• Primary Completion: 2018-03
• Study Completion: 2018-04

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: Female
• Target Recruitment: 2400

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

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Docosahexaenoic acid (DHA)	Docosahexaenoic acid (DHA)	Docosahexaenoic acid (DHA) 200 mg capsules, 3 capsules by mouth every day, from early gestation until the end of pregnancy
Placebo	Placebo (for Docosahexaenoic acid (DHA))	Placebo 200 mg capsules, 3 capsules by mouth every day, from early gestation until the end of pregnancy

Primary Outcome Measures

Name	Time	Method
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.	34 weeks of pregnancy	* 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.

Secondary Outcome Measures

Name	Time	Method
Stillbirth	During pregnancy	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.
Intrauterine growth restriction	At delivery	Birth weight less than the 10th percentile of the population standard for the gestational age.
Severe intrauterine growth restriction	At birth	birth weight less than the 2nd percentile of population (according to the current national recommended standard).
Preterm birth	At birth	Birth \< week 37th, \< week 32th, \< week 28th
Perinatal death	From the 20th gestational week to the 28th day of life	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.
Neonatal	From birth to the 28th day of life	Death of a baby that occurred during the first 28 days of life
Respiratory Distress Syndrome (RDS)	Until the 28th day of life	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.
Bronchopulmonary Dysplasia (BPD)	Until the 28th day of life	Defined as requiring oxygen supplementation at 28 days postnatal age
Intraventricular Hemorrhage (IVH)	Until the 28th day of life	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
Proven Early onset Sepsis	Within the first 48 hours of life	Within first 48hr of life, confirmed by positive blood or cerebrospinal fluid cultures
Necrotizing Enterocolitis	Until the 28th day of life	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.)
Low birth weight	At birth	Number of Infants with a birth weight \< 1500 grams, number of Infants with a birth weight \< 2500 grams
Admitted to Neonatal Intensive Care Unit (NICU)	Until the 28th day of life
Birth biometry	At birth	Measurement of ponderal index (birth weight/height\^3×100), head circumference (cm), Birth weight (grams).
Cesarean section	At delivery	Number of deliveries by cesarean section
Postpartum bleeding	Postpartum period	Estimated bleeding more than 500 ml after vaginal birth or 1000 ml after cesarean section
Postpartum depression	At the 6th postpartum week	Postpartum Depression defined by the Edinburgh Postnatal Depression Scale (EPDS)
Preeclampsia	From pregnancy to discharge after delivery	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.
Gestational Diabetes (GDM)	During pregnancy	Screening during pregnancy
Premature rupture of membranes	During pregnancy	Rupture of the amniotic sac before the onset of labor
Maternal Venous Thrombosis	During pregnancy	Venous Thrombosis confirmed by imaging during pregnancy
Bleeding during pregnancy	During pregnancy	Genital bleeding diagnosed during pregnancy
Placental Abruptio	During pregnancy	Prematurely detachment of a normal positioned placenta for the wall of uterus

Trial Locations

Locations (5)

Centro de Salud Familiar ANCORA Madre Teresa de Calcuta; 🇨🇱 Santiago, Chile

Centro de Salud Familiar ANCORA Juan Pablo II; 🇨🇱 Santiago, Chile

Centro de Salud Familiar ANCORA San Alberto Hurtado; 🇨🇱 Santiago, Chile

Centro Medico Lira 85; 🇨🇱 Santiago, Chile

Centro Medico San Joaquin; 🇨🇱 Santiago, Chile